Antibiotics

ABSTRACT

Novel cephalosporin and penicillin antibiotic derivatives.

This is a division, of application Ser. No. 482,264, filed 6-14-74, nowU.S. Pat. No. 3,948,904.

FIELD OF INVENTION

This invention relates to novel cephalosporin and penicillin derivativesuseful as antibiotics and processes for their peparation.

SUMMARY OF INVENTION

Compounds of the following general Formula I are useful as antibioticagents: ##SPC1##

Wherein Aryl is selected from phenyl or 2-thienyl; Y is selected fromhydrogen, chlorine, bromine, a straight or branched lower alkyl group offrom 1 to 4 carbon atoms, or an alkoxy group of from 1 to 4 carbon atomswith the proviso that when Aryl is 2-thienyl, Y is hydrogen; each of R¹,R² and R³ is selected from hydrogen or a straight or branched loweralkyl group of from 1 to 4 carbon atoms; Z is selected from a bond,oxygen, sulfur or imino with the proviso that when Aryl is 2-thienyl, Zis a bond; W is selected from hydrogen, methyl, amino, hydroxy, SO₃ H,or COOR⁴ wherein R⁴ is selected from hydrogen or 5-indanyl; n is zero, 1or 2 with the proviso that when W is other than hydrogen or methyl and Zis other than a bond, n is not zero; R⁵ is selected from hydrogen ormethoxy; R⁶ is selected from the moiety ##STR1## wherein M is selectedfrom hydrogen; a pharmaceutically acceptable non-toxic anion or cationcharge; alkanoyloxymethyl wherein the alkanoyl moiety contains from 1 to5 carbon atoms and may be straight or branched, alkanoylaminomethylwherein the alkanoyl moiety contains from 1 to 5 carbon atoms and may bestraight or branched and wherein the amino nitrogen may be substitutedwith an alkyl group of from 1 to 4 carbon atoms,alkoxycarbonylaminomethyl wherein the alkoxy moiety contains from 1 to 4carbon atoms and may be straight or branched and wherein the aminonitrogen may be substituted with an alkyl group of from 1 to 4 carbonatoms, p-(alkanoyloxy)benzyl wherein the alkanoyl moiety contains from 1to 5 carbon atoms and may be straight or branched oraminoalkanoyloxymethyl wherein the alkanoyl moiety contains from 2 to 15carbon atoms, and the amino nitrogen may be mono- or disubstituted witha lower alkyl group of from 1 to 4 carbon atoms. X is selected fromhydrogen, acetoxy, 1,3,4 -thiadiazol-5-ylthio,3-methyl-1,2,4-thiadiazol-5-ylthio, tetrazol-5-ylthio,1-methyltetrazol-5-ylthio, 2-methyl-1,3,4-oxadiazol-5-ylthio, or2-methyl-1,3,4-thiadiazol-5-ylthio; and pharmaceutically acceptablesalts thereof.

DETAILED DESCRIPTION OF INVENTION

In general Formula I the substituent groups as represented by M inaddition to being hydrogen or a pharmaceutically acceptable non-toxicanion or cation charge may also be alkanoyloxymethyl as represented bythe structure ##STR2## wherein R⁷ is selected from a straight orbranched lower alkyl group of from 1 to 4 carbon atoms;alkanoylaminomethyl or alkoxycarbonylaminomethyl as represented by thestructure ##STR3## wherein R⁸ represents a straight or branched loweralkyl group of from 1 to 4 carbon atoms or a straight or branched alkoxygroup of from 1 to 4 carbon atoms and R⁹ represents hydrogen or a loweralkyl group of from 1 to 4 carbon atoms; p-(alkanoyloxy)benzyl asrepresented by the structure ##SPC2##

wherein R¹⁰ is a straight or branched lower alkyl of from 1 to 4 carbonatoms, or aminoalkanoyloxymethyl as represented by the group ##STR4##wherein n is 0 to 5, each of R¹¹ and R¹² is selected from hydrogen orlower alkyl of from 1 to 4 carbon atoms, and each of R¹³ and R¹⁴ isselected from hydrogen or a straight or branched lower alkyl group offrom 1 to 4 carbon atoms.

Illustrative examples of straight or branched lower alkyl groups of from1 to 4 carbon atoms which Y, R¹, R², R³, R⁷, R⁸, R¹⁰, R¹³ and R¹⁴ mayrepresent are methyl, ethyl, n-propyl, isopropyl, n-butyl andtert-butyl.

Examples of lower alkyl groups of from 1 to 4 carbon atoms which R⁹, R¹¹and R¹² may represent are methyl, ethyl, n-propyl and n-butyl.

Examples of lower alkoxy groups which Y may represent are methoxy,ethoxy, n-propoxy and n-butoxy.

Illustrative examples of straight or branched lower alkoxy groups whichR⁸ may represent are methoxy, ethoxy, n-propoxy, isopropoxy, sec-butoxy,and n-butoxy.

In general Formula I the substituent group X may represent in additionto hydrogen or acetoxy, a heterocyclicthio group selected from1,3,4-thiadiazol-5-ylthio, 3-methyl-1,2,4-thiadiazol-5-ylthio,tetrazol-5-ylthio, 1-methyltetrazol-5-ylthio,2-methyl-1,3,4-oxadiazol-5-ylthio, or 2-methyl-1,3,4-thiadiazol-5-ylthioas represented by the following respective structures: ##SPC3##

When the Aryl group in the compounds of general Formula I representsphenyl, each of the isothioureamethyl substituent and the Y substituentmay be individually attached to any of the positions 2 through 6 of thephenyl ring. Compounds of this type may be represented by the followinggeneral Formula II. ##SPC4##

The preferred positions of attachment of the isothioureamethylsubstituent in the above Formula II are the ortho- and para- positionsof the phenyl ring. In the above Formula II the substituents asrepresented by Y, R¹, R², R³, Z, n, W, R⁵ and R⁶ have the meaningsdefined in general Formula I.

When the Aryl group in the compounds of general Formula I represents2-thienyl, Y is hydrogen, and Z is a bond. Compounds of this type may berepresented by the following Formula III ##SPC5##

In the compounds of the above Formula III the isothiourea substituentgroup may be attached at the 4 or 5 position of the thienyl group. Inthe above Formula III the substituents as represented by R¹, R², R³ n,W, R⁵ and R⁶ have the meanings defined in general Formula I.

It is apparent from the foregoing description of general Formula I thatthe compounds of this invention are either penicillin derivatives whenR⁶ represents the moiety ##STR5## or cephalosporin derivatives when R⁶represents the moiety ##STR6## wherein M and X have the meanings definedin general Formula I.

The cephalosporin derivatives which represent a preferred embodiment ofthis invention may be represented by the following Formula IV. ##SPC6##

wherein Aryl is selected from phenyl or 2-thienyl; Y is selected fromhydrogen, chlorine, bromine, a straight or branched lower alkyl group offrom 1 to 4 carbon atoms, or an alkoxy group of from 1 to 4 carbonatoms, with the proviso that when Aryl is 2-thienyl, Y is hydrogen; eachof R¹, R² and R³ is selected from hydrogen or a straight or branchedlower alkyl group of from 1 to 4 carbon atoms; Z is selected from abond, oxygen, sulfur or imino with the proviso that when Aryl is2-thienyl, Z is a bond; W is selected from hydrogen, methyl, amino,hydroxy, SO₃ H, or COOR⁴ wherein R⁴ is selected from hydrogen or5-indanyl; n is zero, 1 or 2 with the proviso that when W is other thanhydrogen or methyl, and Z is other than a bond, n is not zero; R⁵ isselected from hydrogen or methoxy; M is selected from hydrogen, apharmaceutically acceptable non-toxic anion or cation charge,alkanoyloxy methyl wherein the alkanoyl moiety contains from 1 to 5carbon atoms and may be straight or branched, alkanoylaminomethylwherein the alkanoyl moiety contains from 1 to 5 carbon atoms and may bestraight or branched and wherein the amino nitrogen may be substitutedwith an alkyl group of from 1 to 4 carbon atoms,alkoxycarbonylaminomethyl wherein the alkoxy moiety contains from 1 to 4carbon atoms and may be straight or branched and wherein the aminonitrogen may be substituted with an alkyl group of from 1 to 4 carbonatoms, p-(alkanoyloxy)benzyl wherein the alkanoyl moiety contains from 1to 5 carbon atoms and may be straight or branched; oraminoalkanoyloxymethyl wherein the alkanoyl moiety contains from 2 to 15carbon atoms and the amino nitrogen may be mono- or disubstituted with alower alkyl group of from 1 to 4 carbon atoms; X is selected fromhydrogen, acetoxy, 1,3,4-thiadiazol-5-ylthio,3-methyl-1,2,4-thiadiazol-5-ylthio, tetrazol-5-ylthio,1-methyltetrazol-5-ylthio, 2-methyl-1,3,4-oxadiazol-5-ylthio, or2-methyl-1,3,4-thiadiazol-5-ylthio; and pharmaceutically acceptablesalts thereof.

The penicillin derivatives which represent a preferred embodiment ofthis invention may be represented by the following formula V: ##SPC7##

wherein Aryl is phenyl or 2-thienyl; Y is selected from hydrogen,chlorine, bromine, a straight or branched lower alkyl group of from 1 to4 carbon atoms, or an alkoxy group of from 1 to 4 carbon atoms with theproviso that when Aryl is 2-thienyl, Y is hydrogen; each of R¹, R² andR³ is selected from hydrogen or a lower alkyl group of from 1 to 4carbon atoms; Z is selected from a bond, oxygen, sulfur or imino withthe proviso that when Aryl is 2-thienyl, Z is a bond; W is selected fromhydrogen, methyl, amino, hydroxy, SO₃ H or COOR⁴ wherein R⁴ is selectedfrom hydrogen or 5-indanyl; n is zero, 1 or 2 with the proviso that whenW is other than hydrogen or methyl and Z is other than a bond, n is notzero; R⁵ is selected from hydrogen or methoxy; M is selected fromhydrogen, a pharmaceutically acceptable non-toxic anion or cationcharge, alkanoyloxymethyl wherein the alkanoyl moiety contains from 1 to5 carbon atoms and may be straight or branched, alkanoylaminomethylwherein the alkanoyl moiety contains from 1 to 5 carbon atoms and may bestraight or branched and wherein the amino nitrogen may be substitutedwith an alkyl group of from 1 to 4 carbon atoms,alkoxycarbonylaminomethyl wherein the alkoxy moiety contains from 1 to 4carbon atoms and may be straight or branched and wherein the aminonitrogen may be substituted with an alkyl group of from 1 to 4 carbonatoms, p-(alkanoyloxy)benzyl wherein the alkanoyl moiety contains from 1to 5 carbon atoms and may be straight or branched; oraminoalkanoyloxymethyl wherein the alkanoyl moiety contains from 2 to 15carbon atoms, and the amino nitrogen may be mono- or di-substituted witha lower alkyl group of from 1 to 4 carbon atoms; and pharmaceuticallyacceptable salts thereof.

In the compounds of Formulas IV and V it is apparent that the R⁵substituent may be either cis or trans to the hydrogen atom at the6-position of the cephalosporin in derivatives of Formula IV and at the5-position of the penicillin derivatives of Formula V. The compounds ofFormulas IV and V wherein the R⁵ substituent is cis to theaforementioned hydrogen atoms are preferred.

Other preferred embodiments of this invention are: (A) compounds whereinW represents hydrogen, hydroxy, amino, SO₃ H, and COOR⁴ wherein R⁴represents hydrogen in that such substitution results in compoundshaving broader spectrum of activity and/or improved oral activity forexample compounds wherein

1. W represents hydroxy are more resistant to β-lactamase organisms;

2. W represents SO₃ H or COOR⁴ wherein R⁴ represents hydrogen havebroader gram negative spectrum;

3. W represents NH₂ have improved oral activity; (B) compounds whereinR⁵ represents methoxy are of particular interest in that such compoundsdemonstrate antibacterial activity against cephalosporinase producinggram negative organisms.

C. compounds wherein X represents acetoxy,2-methyl-1,3,4-thiadiazol-5-ylthio or 1-methyltetrazol-5l -ylthio.

Of the preferred embodiments set forth in (A), (B) and (C) compoundswherein Z represents a bond, are more preferred.

The most preferred compounds of this invention are those represented bythe following Formula VI ##SPC8##

wherein W' is selected from hydrogen, hydroxy, amino, COOH or SO₃ H; X'is selected from hydrogen, acetoxy, 2-methyl-1,3,4-thiadiazol-5-ylthioor 1-methyltetrazol-5-ylthio; and pharmaceutically acceptable saltsthereof.

In the above Formula VI compounds wherein the hydrogen atoms at the 6-and 7- positions are cis to one another are preferred.

The individual optical isomers of the compounds of this inventionwherein W is other than hydrogen are also included within the scope ofthis invention.

The non-toxic acid addition salts of the compounds of this inventionsuch as mineral acid addition salts, for example, hydrogen chloride,hydrogen bromide, hydrogen iodide, sulfate, sulfamate and phosphate andorganic acid addition salts, for example, maleate, acetate, citrate,oxalate, succinate, benzoate, tartrate, fumarate, malate, mandelate andascorbate, are also included within the scope of this invention.

Also within the scope of this invention are the nontoxicpharmaceutically acceptable salts of the compounds of this inventionwherein W represents COOH or SO₃ H and compounds wherein M representshydrogen. Illustrative pharmaceutically acceptable salts of these acidderivatives are primary, secondary or tertiary amines, for example,cyclohexylamine, ethylamine and pyridine.

The pharmaceutically acceptable cations which may be present as thegroup M in the compounds of general Formulas I to VI include alkalimetal ions, for example sodium ion, potassium ion, calcium ion as wellas ammonium, and organic amine cations, for example, lower alkylammonium groups, such as triethylammonium, and N-ethylpiperidine.

The salt forms of compounds of Formulas I to VI wherein M is apharmaceutically acceptable cation are prepared in the manner recognizedin the art and may be formed in situ or by reacting the correspondingacid with base for example sodium bicarbonate or triethylamine.

The compounds of this invention may be administered in a manner similarto that of many well known cephalosporin compounds, for example,cephalexin, cephalothin, or cephaloglycine. They may be administeredalone or in the form of pharmaceutical preparations either orally,parenterally and topically to warm blooded animals, that is, birds andmammals, for example, cats, dogs, cattle, and horses, and humans. Fororal administration the compounds may be administered in the form oftablets, capsules or pills or in the form of elixirs or suspensions. Forparenteral administration they are best used in the form of a sterileaqueous solution which may contain other solutes, for example, enoughsaline or glucose to make the solution isotonic. For topicaladministration the compounds may be incorporated into creams orointments.

Illustrative examples of bacteria against which the compounds of thisinvention are active are Staphylococcus aureus, Salmonellaschottmuelleri, Klebsiella pneumoniae, Diplococcus pneumonia, andStreptococcus pyogenes.

An illustrative example of a cephalosporin derivative of this inventionis3-[(acetyloxy)methyl]-7-[[2-[4-(isothioureamethyl)phenyl]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid. An illustrative example of a penicillin derivative of thisinvention is6-[[2-[4-(isothioureamethyl)phenyl]acetyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid. Additional examples of compounds of this invention are set forthhereinbelow in the specific compounds which are representative of theinvention.

The compounds of Formula I wherein R⁴ is hydrogen may be prepared bytreating a derivative of the formula ##SPC9##

with a derivative of the formula ##STR7## wherein Aryl is selected fromphenyl or 2-thienyl; halo is selected from chlorine or bromine; Y isselected from hydrogen, chlorine, bromine, a straight or branched loweralkyl group of from 1 to 4 carbon atoms, or an alkoxy group of from 1 to4 carbon atoms with the proviso that when Aryl is 2-thienyl, Y ishydrogen; Z is selected from a bond, oxygen, sulfur, or imino with theproviso that when Aryl is 2-thienyl, Z is a bond; W² is selected fromhydrogen, methyl, amino, hydroxy, SO₃ H or COOH; n is zero, 1 or 2 withthe proviso that when W² is other than hydrogen or methyl and Z is otherthan a bond, n is not zero; R⁵ is selected from hydrogen or methoxy; R⁶is selected from the moiety ##STR8## wherein M is selected fromhydrogen; a pharmaceutically acceptable non-toxic anion or cationcharge; alkanoyloxymethyl wherein the alkanoyl moiety contains from 1 to5 carbon atoms and may be straight or branched, alkanoylaminomethylwherein the alkanoyl moiety contains from 1 to 5 carbon atoms and may bestraight or branched and wherein the amino nitrogen may be substitutedwith an alkyl group of from 1 to 4 carbon atoms,alkoxycarbonylaminomethyl wherein the alkoxy moiety contains from 1 to 4carbon atoms and may be straight or branched and wherein the aminonitrogen may be substituted with an alkyl group of from 1 to 4 carbonatoms, p-(alkanoyloxy)benzyl wherein the alkanoyl moiety contains from 1to 5 carbon atoms and may be straight or branched oraminoalkanoyloxymethyl wherein the alkanoyl moiety contains from 2 to 15carbon atoms, and the amino nitrogen may be mono- or disubstituted witha lower alkyl group of from 1 to 4 carbon atoms; X is selected fromhydrogen, acetoxy, 1,3,4-thiadiazol-5-ylthio,3-methyl-1,2,4-thiadiazol-5-ylthio, tetrazol-5-ylthio,1-methyltetrazol-5-ylthio, 2-methyl-1,3,4-oxadiazol-5-ylthio, or2-methyl-1,3,4-thiadiazol-5-ylthio; each of R¹, R² and R³ is selectedfrom hydrogen or a straight or branched lower alkyl group of from 1 to 4carbon atoms.

The above reaction is carried out in an alcoholic solvent attemperatures of from 0° C to 100° C, preferably from 25° to 50° C, forfrom 1/2 hour to 6 hours yielding the corresponding isothiouroniumhydrochloride derivative in solution. The organic solvent is evaporated,and the residual oil is triturated with appropriate organic solventssuch as ether, hexane, ethyl acetate or acetonitrile, to give theisothioureamethyl substituted compound.

When the substituent group W² in the above Formula VII represents anamino group, suitable blocking groups, e.g., an acid salt such ashydrochloride salt, an acyl group, or tert-butoxycarbonyl may beemployed to protect the amino function. Such blocking groups are removedafter the coupling reaction by methods generally known in the art, e.g.,as described by Lemieux et al., in U.S. Pat. No. 3,657,232.

Illustrative examples of compounds of Formula VIII are isothiourea,1-ethyl-3-n-propylisothiourea, 1-ethyl-3-n-butylisothiourea,1,1-di-n-propyl-3-ethylisothiourea, 1-ethyl-3-isopropylisothiourea,1,1,3-triethylisothiourea, 1,1-di-n-propyl-3-methylisothiourea, 1,3-di-sec-butylisothiourea, 1,3-di-n-propylisothiourea,1-n-butyl-3-methylisothiourea, 1-ethyl-3-methylisothiourea,1,1-diethyl-3-methylisothiourea, 1,3-diethylisothiourea,1-ethylisothiourea, 3-n-propylisothiourea, 1,3-dimethylisothiourea, 1,3-diisopropylisothiourea, 1,3-di-n-butylisothiourea,1-methyl-3-ethylisothiourea, and 1,1-dimethyl-3-ethylisothiourea.

Compounds of general Formula VII may be prepared by coupling aderivative of the formula ##SPC10##

with an acid of the formula ##STR9## or a functional derivative thereofwherein Aryl, halo, Y, Z, n, W², R⁵ and R⁶ have the meanings defined ingeneral Formula VII.

When the substituent group W² in the above Formula X represents an aminogroup suitable blocking groups, e.g., an acid salt such as hydrochloridesalt, tert-butoxycarbonyl, or carbobenzyloxy are employed to protect theamino function in a manner similar to that described hereinabove.

Functional equivalents of the acids as represented by Formula X includethe acid halides, for example, the acid chloride, acid anhydrides,including mixed anhydrides with, for example, alkylphosphoric acids,lower aliphatic monoesters of carbonic acid, or alkyl or aryl sulfonicacids. Additionally, the acid azide or an active ester or thioester, forexample, with p-nitrophenol, 2,4-dinitrophenol, or thioacetic acid, maybe used, or the free acid as represented by Formula X may be coupledwith the 7-aminocephalosporanic acid derivative or a 6-aminopenicillanicacid derivative as represented by Formula VIII after first reacting theacid with N,N'-dimethylchloroforminium chloride or by use of acarbodiimide reagent, for example, N,N'-diisopropylcarbodiimide,N,N'-dicyclohexylcarbodiimide, orN-cyclohexyl-N'-(2-morpholinoethyl)carbodiimide.

The coupling reaction is generally carried out in the presence of asolvent. Suitable solvents include ethyl acetate, acetone, dioxane,acetonitrile, chloroform, methylene chloride, tetrahydrofuran anddimethyl formamide. As hydrophilic solvents are employed mixtures ofthese solvents with water are also suitable for the above reaction. Thecoupling reaction may be carried out in the presence of a base, forexample, an alkaline bicarbonate. The temperature of the reaction mayvary from -10° to 100° C, and the reaction time may vary from about 1/2hour to 10 hours. The cephalosporin products are isolated byconventional methods.

The compounds of general Formula VII may also be prepared by combining amodified polystyrene containing nitrophenol or hydroxysuccinimide groupswith an acid of general Formula X and mixing the activated acid thusformed with a compound of general Formula IX by the general proceduredescribed in Canadian Patent No. 892,580, issued Feb. 8, 1972, bysubstituting a compound of general Formula IX for the penicillanic acidderivatives described therein.

The compounds of Formula IX may be more fully described by the followingFormulas XI and XII ##SPC11##

wherein R⁵, M and X have the meanings defined in Formula I. Compounds ofFormulas XI and XII wherein R⁵ is hydrogen, M is hydrogen or apharmaceutically acceptable non-toxic anion or cation and X is hydrogenor acetoxy are commercially available or may be prepared by methods wellknown in the art. The corresponding compounds wherein R⁵ is methoxy maybe prepared by the general procedures described in U.S. Pat. No.3,778,432.

Compounds of Formulas XI and XII wherein M is alkanoyloxymethyl may beprepared by reacting the corresponding acid in the form of a salt, suchas an alkali metal salt or the triethylammonium salt with a compound ofthe formula ##STR10## wherein halo is chlorine or bromine and R⁷ is astraight or branched lower alkyl group of from 1 to 4 carbon atoms bythe general procedure described in U.S. Pat. No. 3,655,658.

Compounds of Formulas XI and XII wherein M is alkanoylaminomethyl oralkoxycarbonylaminomethyl are prepared by treating the sodium salt ofacid derivatives of Formula XI and XII in an organic solvent such asdimethyl formamide or hexamethylphosphoramide, at room temperature withan equivalent amount of an alkanoylaminomethyl halide or analkoxycarbonylaminomethyl halide for 1/2 to 3 hours after which themixture is poured into ice-water. The resulting precipitated product isisolated by standard procedures.

Compounds of Formulas XI and XII wherein M is p-(alkanoyloxy)benzyl areprepared by adding 2-equivalents of the p-(alkanoyloxy)benzyl alcohol toa suspension of the sodium salt of acid derivatives of Formulas XI andXII in dimethyl formamide or hexamethylphosphoramide after which themixture is cooled to 0° C. 1.2 equivalents of dicyclohexylcarbodiimidein dimethyl formamide is added dropwise to the mixture with stirring.The mixture is stirred at 0° C for 1/2 to 3 hours and then an additional2 to 5 hours at room temperature. The formed dicyclohexylurea is removedby filtration and the filtrate is diluted with chloroform, methylenechloride, or ethyl acetate, washed with water and dried to give theproduct.

Compounds of Formulas XI and XII wherein M is aminoalkanoyloxymethyl areprepared by mixing a suspension of the sodium salt of an acid of FormulaXI and XII and an excess of an appropriate amine protectedaminoalkanoyloxymethyl halide in a solvent such as dimethyl formamide,hexamethylphosphoramide or dimethyl sulfoxide for 2 to 96 hours. Themixture is then diluted with a solvent such as ethyl acetate ormethylene chloride, washed with water, aqueous base, then water. Theorganic phase is separated and the precipitate isolated by conventionalmeans followed by deprotection of the amine group to give the product.

Compounds of Formula XII wherein X is a heterocyclicthio group asdescribed in Formula VI are prepared by dissolving 1 equivalent of theacid in the form of a salt, such as, the sodium salt wherein X isacetoxy in about 500 to 2000 ml of water at from 50° to 80° C under anitrogen atmosphere and subsequently adding 1 equivalent of a base, suchas, triethylammonium or sodium bicarbonate and 1 to 3 equivalents of theheterocyclic-thiol. The reaction mixture is stirred at 50° to 90° C forabout 2 to 6 hours after which the water is evaporated, and the residueis taken up in an organic solvent, such as, methanol, ethanol, ordimethyl formamide, and precipitated with an organic solvent, such as,acetonitrile, acetone, ethyl acetate or chloroform.

In a similar manner the cephalosporin in derivatives of this inventionwherein X represents a heterocyclicthio group selected from1,3,4-thiadiazol-5-ylthio, 3-methyl-1,2,4-thiadiazol-5-ylthio,tetrazol-5-ylthio, 1-methyltetrazol-5-ylthio,2-methyl-1,3,4-oxadiazol-5-ylthio, or 2-methyl-1,3,4-thiadiazol-5-ylthioand M represents hydrogen may be prepared by reacting the3-[(acetyloxy)methyl]-derivative with the appropriate heterocyclicthiolgroup as represented by the following: ##SPC12##

In the above Formulas XV and XVI Aryl is selected from phenyl or2-thienyl; Y is selected from hydrogen, chlorine, bromine, a straight orbranched lower alkyl group of from 1 to 4 carbon atoms, or an alkoxygroup of from 1 to 4 carbon atoms with the proviso that when Aryl is2-thienyl, Y is hydrogen; each of R¹, R² and R³ is selected fromhydrogen or a straight or branched lower alkyl group of from 1 to 4carbon atoms; Z is selected from a bond, oxygen, sulfur or imino withthe proviso that when Aryl is 2-thienyl, Z is a bond; W is selected fromhydrogen, methyl, amino, hydroxy, SO₃ H, or COOR⁴ wherein R⁴ is selectedfrom hydrogen or 5-indanyl; n is zero, 1 or 2 with the proviso that whenW is other than hydrogen or methyl and Z is other than a bond, n is notzero; R⁵ is selected from hydrogen or methoxy; and the moiety -S-heterois selected from 1,3,4-thiadiazol-5-ylthio,3-methyl-1,2,4-thiadiazol-5-ylthio, tetrazol-5-ylthio,1-methyltetrazol-5-ylthio, 2-methyl-1,3,4-oxadiazol-5-ylthio, or2-methyl-1,3,4-thiadiazol-5-ylthio.

In the above reaction one equivalent of the sodium salt derivative isdissolved in water at a temperature of from 25° to 90° C under anitrogen atmosphere followed by the addition of one equivalent of a basesuch as triethylammonium or sodium bicarbonate and from one to threeequivalents of the heterothiol derivative after which the reactionmixture is stirred for about 2 to 6 hours at a temperature of from 25°to 90° C.

The compounds of Formula X are prepared by direct halomethylation asdescribed hereinbelow of an acid of the formula ##STR11## wherein Aryl,Y, Z, n and W^(a) have the meanings defined in Formula VII which arecommercially available or are obtained by methods well known in the art.

When the substituent group W² in compounds of Formula XIII representsamino, the amino group is protected by a suitable blocking group, forexample an acyl group, such as, acetyl or trifluoroacetyl, prior to thehalomethylation reaction. Upon completion of the halomethylationreaction the blocking groups may be removed by acid hydrolysis byprocedures known in the art.

The halomethylated derivatives of the compounds of Formula XIII areobtained by several methods. For example, a compound of Formula XIIIwith a source of formaldehyde such as paraformaldehyde, ClCH₂ OCH₃, orformalin solution, in the presence of a Lewis acid, such as ZnCl₂, AlCl₃SnCl₄, or ClSO₃ H in a solvent, such as petroleum ether, chloroform,carbon tetrachloride, or benzene at a temperature ranging from -10° to100° C during which time hydrogen chloride gas or hydrogen bromide gasis bubbled into the reaction mixture, compounds of general Formula X areobtained.

The reaction of an acid Formula XIII with 34-38% formalin inconcentrated hydrochloric acid at temperatures ranging from -10° to 100°C during which time hydrogen chloride gas or hydrogen bromide gas isbubbled through the reaction mixture also yields compounds of generalFormula X.

Additionally upon reaction of an acid of Formula XIII with trioxane inacetic acid or phosphoric acid at temperatures of from -10° to 100° Cduring which time hydrogen bromide or hydrogen chloride gas is bubbledthrough the reaction mixture, compounds of general Formula X areobtained. Or, the reaction of an acid of Formula XIII in the presence ofa Lewis acid, such as those described hereinabove, with chloromethylether at temperatures from -10° and 100° C, or the reaction of the acidin acetic acid or concentrated sulfuric acid with dichloromethyl etherin the presence of zinc chloride will give compounds of general FormulaX.

The compounds of Formula X wherein W² represents COOH, and Aryl isphenyl are preferably obtained by treating the corresponding diethylester of Formula XIII with 40% formalin in the presence of anhydrouszinc chloride in benzene at about 50° C during which time hydrogenchloride or hydrogen bromide gas is bubbled into the reaction mixturefollowed by acid hydrolysis.

Compounds of Formula X wherein W² represents SO₃ H may be obtained bythe halomethylation reactions described above using an acid of FormulaXIII wherein W² represents SO₃ H or the carboxy methyl ester thereof inwhich latter case the resulting halomethylated compound is converted tothe free COOH by acid hydrolysis.

In the halomethylation of compounds of Formula XIII wherein W²represents OH it may be advantageous to protect the OH group prior tohalomethylation as described by V. Reichert, et al., Pharmazie 5, 10(1950).

The compounds of this invention wherein R⁴ is hydrogen may also beprepared by coupling a derivative of the formula ##SPC13##

with an acid of the formula ##STR12## or a functional derivative thereofwherein R⁵ is selected from hydrogen or methoxy; R⁶ is selected from themoiety ##STR13## wherein M is selected from hydrogen; a pharmaceuticallyacceptable non-toxic anion or cation charge; alkanoyloxymethyl whereinthe alkanoyl moiety contains from 1 to 5 carbon atoms and may bestraight or branched, alkanoylaminomethyl wherein the alkanoyl moietycontains from 1 to 5 carbon atoms and may be straight or branched andwherein the amino nitrogen may be substituted with an alkyl group offrom 1 to 4 carbon atoms, alkoxycarbonylaminomethyl wherein the alkoxymoiety contains from 1 to 4 carbon atoms and may be straight or branchedand wherein the amino nitrogen may be substituted with an alkyl group offrom 1 to 4 carbon atoms, p-(alkanoyloxy)benzyl wherein the alkanoylmoiety contains from 1 to 5 carbon atoms and may be straight or branchedor aminoalkanoyloxymethyl wherein the alkanoyl moiety contains from 2 to15 carbon atoms, and the amino nitrogen may be mono- or disubstitutedwith a lower alkyl group of from 1 to 4 carbon atoms; X is selected fromhydrogen, acetoxy, 1,3,4-thiadiazol-5-ylthio,3-methyl-1,2,4-thiadiazol-5-ylthio, tetrazol-5-ylthio,1-methyltetrazol-5-ylthio, 2-methyl-1,3,4-oxadiazol-5-ylthio, or2-methyl-1,3,4-thiadiazol-5-ylthio; Aryl is selected from phenyl or2-thienyl; Y is selected from hydrogen, chlorine, bromine, a straight orbranched lower alkyl group of from 1 to 4 carbon atoms, or an alkoxygroup of from 1 to 4 carbon atoms with the proviso that when Aryl is2-thienyl, Y is hydrogen; each of R¹, R² and R³ is selected fromhydrogen or a straight or branched lower alkyl group of from 1 to 4carbon atoms; Z is selected from a bond, oxygen, sulfur or imino withthe proviso that when Aryl is 2-thienyl, Z is a bond; W² is selectedfrom hydrogen, methyl, amino, hydroxy, SO₃ H, or COOH; n is zero, 1 or 2with the proviso that when W² is other than hydrogen or methyl and Z isother than a bond, n is not zero.

When the substituent group W² in the above Formula XIV represents anamino group suitable blocking groups, e.g., a mineral salt such ashydrochloride salt, tert-butoxycarbonyl, or carbobenzyloxy are employedto protect the amino function in a manner similar to that describedhereinabove.

Functional equivalents of the acids as represented by Formula XIVinclude the acid halides, for example, the acid chloride, acidanhydrides, including mixed anhydrides with, for example,alkylphosphoric acids, lower aliphatic mono-esters of carbonic acid, oralkyl or aryl sulfonic acids. Additionally, the acid azide or an activeester or thio-ester, for example, with p-nitrophenol, 2,4-dinitrophenol,or thioacetic acid, may be used, or the free acid as represented byFormula XIV may be coupled with the 7-aminocephalosporanic acidderivative or a 6-aminopenicillanic acid derivative as represented byFormula IX after first reacting the acid withN,N'-dimethylchloroforminium chloride or by use of a carbodiimidereagent, for example, N,N'-diisopropylcarbodiimide,N,N'-dicyclohexylcarbodiimide, orN-cyclohexyl-N'-(2-morpholinoethyl)carbodiimide.

The coupling reaction is generally carried out in the presence of asolvent. Suitable solvents include ethyl acetate, acetone, dioxane,acetonitrile, chloroform, methylene chloride, tetrahydrofuran anddimethylformamide. As hydrophilic solvents are employed mixtures ofthese solvents with water are also suitable for the above reaction. Thecoupling reaction is generally carried out in the presence of a base,for example, an alkaline bicarbonate. The temperature of the reactionmay vary from -10° to 100° C, and the reaction time may vary from about1/2 hour to 10 hours. The cephalosporin products are isolated byconventional methods.

The preparation of compounds of Formula IX is described hereinabove.

Compounds of Formula I wherein R⁴ is 5-indanyl are prepared by reactingthe corresponding acid, that is, compounds of Formula I wherein R⁴ ishydrogen with 5-indanol in an inert solvent in the presence ofN,N'-dicyclohexylcarbodiimide at a pH of about 2.5 and a temperature offrom 20° to 30° C. Equimolar amounts of the reactants are employed or aslight excess of the 5-indanol may be used. The molar amount ofN,N'-dicyclohexylcarbodiimide employed is equivalent to the molar amountof 5-indanol. Suitable solvents for the reaction are dioxane,tetrahydrofuran, ethyl acetate, dimethyl formamide and methylenechloride.

Compounds of Formula I wherein M represents alkanoylaminomethyl oralkoxycarbonylaminomethyl and W is other than COOH may also be preparedby reacting the corresponding acid in the form of a salt such as analkali metal salt, for example, the sodium salt with 1.5 to 2.5equivalents of an appropriate alkanoylaminomethyl halide oralkoxycarbonylaminomethyl halide each of which may be represented by thestructure ##STR14## wherein halo is selected from a reactive halogenatom such as chlorine or bromine, R⁸ is selected from a straight orbranched lower alkyl group of from 1 to 4 carbon atoms or a straight orbranched lower alkoxy group of from 1 to 4 carbon atoms, and R⁹ ishydrogen or a lower alkyl group of from 1 to 4 carbon atoms. Thereactants are stirred for about 1 to 5 hours in dimethyl formamide,hexamethylphosphoramide or a similar solvent at a temperature rangingfrom 10° to 45° C after which the reaction mixture is poured into icewater and decanted. The oily residue is taken up in an organic solventsuch as ethyl acetate, methylene chloride or benzene, washed with basethen with water and dried over magnesium sulfate. The organic solutionis evaporated to dryness in vacuo to give the desired ester.

Prior to the above esterification reaction compounds wherein Wrepresents amino are protected with blocking groups, for example,tert-butoxycarbonyl or carbobenzyloxy, such groups being removed uponcompletion of the esterification procedure by methods generally known inthe art, for example, by the method set forth in the aforementioned U.S.Pat. No. 3,657,232.

Compounds of Formula I wherein M represents p-(alkanoyloxy)benzyl and Wis other than COOH may also be prepared by reacting molar equivalents ofthe corresponding acid and a p-(alkanoyloxy)benzyl alcohol wherein thealkanoyl moiety contains from 1 to 4 carbon atoms and may be straight orbranched. The reactants are dissolved in an organic solvent such asdimethyl formamide or hexamethylphosphoramide and cooled to atemperature of from -15° C to 25° C after which an equivalent quantityof dicyclohexylcarbodiimide in dimethyl formamide orhexamethylphosphoramide is added dropwise to the reaction mixture withstirring. Stirring is continued for 1/2 to 2 hours at temperatures offrom -15° C to 25° C and then 4 to 6 hours at from 25° to 45° C. Theformed dicyclohexylurea is removed by filtration, and the filtrate isdiluted with chloroform, ethyl acetate or methylene chloride and washedwith water. The organic layer is dried and evaporated to give theproduct.

Compounds of Formula I wherein M is alkanoyloxymethyl and W is otherthan COOH may also be prepared by reacting the corresponding acid in theform of a salt, such as an alkali metal salt or the triethylammoniumsalt with a compound of the formula ##STR15## wherein halo is chlorineor bromine, and R⁷ is a straight or branched lower alkyl group of from 1to 4 carbon atoms by the general procedure described in U.S. Pat. No.3,655,658.

Compounds of Formula I wherein M is aminoalkanoyloxymethyl and W isother than COOH may also be prepared by mixing a suspension of thesodium salt of the corresponding acid and an excess of an appropriateamine protected aminoalkanoyloxymethyl halide in a solvent such asdimethyl formamide, hexamethylphosphoramide or dimethyl sulfoxide for 2to 96 hours. The mixture is then diluted with a solvent such as ethylacetate or methylene chloride, washed with water, aqueous base, thenwater. The organic phase is separated and the precipitate isolated byconventional means followed by deprotection of the amine group to givethe product.

Compounds of Formula XIV may be prepared by reacting derivatives ofFormulas VIII and X by the procedure described on page 14 at lines 9 to16 and these compounds, particularly those wherein W² is other than H orCH₃ are useful in the preparation of compounds of Formula I.

EXAMPLE 1 p-Chloromethylphenylacetyl chloride

A. At a temperature of from -10° to 0° C hydrogen chloride gas isbubbled through a stirred mixture of 102 g of phenylacetic acid, 67.5 gof paraformaldehyde and 67.5 g of zinc chloride in 1000 ml of petroleumether for one hour. Stirring is continued for about one hour at roomtemperature after which the mixture is refluxed for about 2 hours duringwhich time hydrogen chloride gas is bubbled into the mixture. To thereaction mixture is added 1000 ml each of methylene chloride and water.The organic phase is separated and the aqueous phase is extracted twicewith methylene chloride. The combined organic phases are extracted fourtimes with a saturated sodium bicarbonate solution. The organic neutralphase is dried over anhydrous sodium sulfate, filtered and the solventis removed under vacuum to give a neutral by-product which is furtheridentified in Example 5 below. The basic aqueous phase is separated andacidified with cold concentrated hydrochloric acid to pH 2-3, thenextracted three times with methylene chloride. The methylene chloridefraction is dried over anhydrous sodium sulfate, filtered and thesolvent evaporated. The resulting oily acidic product is chromatographedon silica gel using benzene and benzene-acetone as the eluant to givep-chloromethylphenylacetic acid which is recrystallized from hotchloroform. M.P. 147°-149° C.

B. A mixture of 1 g of p-chloromethylphenylacetic acid and 6 ml ofthionyl chloride is stirred at room temperature for 25 hours after whichthe excess thionyl chloride is removed under vacuum to yieldp-chloromethylphenylacetyl chloride.

When in Example 1 (A) an acid selected from Table I is substituted forphenylacetic acid the respective chloromethyl derivative listed in TableI is obtained which can be converted to the acid chloride by theprocedure of Example 1 (B).

                  TABLE 1                                                         ______________________________________                                        Acid            Chloromethyl derivative                                       ______________________________________                                        hydrotropic acid                                                                              p-chloromethylhydrotro-                                                       pic acid                                                      mandelic acid   p-chloromethylmandelic                                                        acid                                                          dihydrocinnamic p-chloromethyldihydro-                                        acid            cinnamic acid                                                 2-methylhydrocin-                                                                             p-chloromethyl-2-methyl-                                      namic acid      hydrocinnamic acid                                            3-phenyllactic  3-(p-chloromethylphenyl)-                                     acid            lactic acid                                                   4-phenylbutyric 4-(p-chloromethylphenyl)-                                     acid            butyric acid                                                  2-methyl-4-phenyl-                                                                            2-methyl-4-(p-chloro-                                         butyric acid    methylphenyl)butyric acid                                     2-hydroxy-4-phenyl-                                                                           2-hydroxy-4-(p-chloro-                                        butyric acid    methylphenyl)butyric acid                                     phenoxyacetic acid                                                                            p-chloromethylphenoxy-                                                        acetic acid                                                   2-phenoxypropionic                                                                            2-(p-chloromethylphenoxy)-                                    acid            propionic acid                                                4-phenoxybutyric                                                                              4-(p-chloromethylphenoxy)-                                    acid            butyric acid                                                  2-methyl-4-phenoxy-                                                                           2-methyl-4-(p-chloro-                                         butyric acid    methylphenoxy)butyric                                                         acid                                                          3-phenoxypropionic                                                                            3-(p-chloromethylphenoxy)-                                    acid            propionic acid                                                3-phenoxylactic 3-(p-chloromethyl-                                            acid            phenoxy)lactic acid                                           anilinoacetic acid                                                                            p-chloromethylanilino                                                         acetic acid                                                   2-hydroxy-2-(2-thi-                                                                           2-hydroxy-2-[2-(5-chloro-                                     enyl)acetic acid                                                                              methyl)thienyl]acetic acid                                    2-anilinopropionic                                                                            2-(p-chloromethyl)anilino-                                                    propionic acid                                                4-anilinobutyric                                                                              4-(p-chloromethylanilino)-                                    acid            butyric acid                                                  3-anilinobutyric                                                                              3-(p-chloromethylanilino)-                                    acid            butyric acid                                                  phenylthioacetic                                                                              p-chloromethylphenyl-                                         acid            thioacetic acid                                               2-phenylthiopro-                                                                              2-(p-chloromethylphenyl)-                                     pionic acid     thiopropionic acid                                            4-phenylthiobutyric                                                                           4-(p-chloromethylphenyl)-                                     acid            thiobutyric acid                                              o-chlorophenyl- o-chloro-p-chloromethyl-                                      acetic acid     phenylacetic acid                                             ______________________________________                                    

EXAMPLE 2 p-Chloromethylphenylglycine hydrochloride

A mixture of 2.03 g of trifluoroacetylated phenylglycine, 0.8 g of zincchloride in chloromethylether is heated at 65° C for 12 hours. Theexcess reagent is removed under vacuum, and the residue is dissolved inCH₂ Cl₂, washed with saturated NaHCO₃ solution then saturated sodiumchloride solution. The neutral organic phase is dried over Na₂ SO₄ andconcentrated to an oil which was purified by column chromatography.Similarly the chloromethyl derivatives listed in Table II may beprepared from the listed acid.

                  TABLE II                                                        ______________________________________                                        Acid            Chloromethyl derivative                                       ______________________________________                                        phenylalanine   p-(chloromethylphenyl)-                                                       alanine HCl                                                   2-amino-4-phenyl-                                                                             2-amino-4-(p-chloro-                                          butyric acid    methylphenyl)butyric                                                          acid HCl                                                      2-amino-4-phenoxy-                                                                            2-amino-4-(p-chloromethyl-                                    butyric acid    phenoxy)butyric acid HCl                                      3-phenoxyalanine                                                                              3-(p-chloromethyl-                                                            phenoxy)alanine HCl                                           2-amino-4-anilino-                                                                            2-amino-4-(p-chloro-                                          butyric acid    methylanilino)butyric                                                         acid HCl                                                      2-amino-4-phenyl-                                                                             2-amino-4-(p-chloro-                                          thiobutyric acid                                                                              methylphenyl)thio-                                                            butyric acid HCl                                              3-phenylthioalanine                                                                           3-(p-chloromethyl-                                                            phenyl)thioalanine HCl                                        2-(2-thienyl)glycine                                                                          2-[2-(5-chloromethyl)-                                                        thienyl]glycine HCl                                           2-amino-3-(2-thienyl)-                                                                        2-amino-3-[2-(5-chloro-                                       propionic acid  methyl)thienyl]pro-                                                           pionic acid HCl                                               2-amino-4-(2-thienyl)-                                                                        2-amino-4-[2-(5-chloro-                                       butyric acid    methyl)thienyl]butyric                                                        acid HCl                                                      ______________________________________                                    

EXAMPLE 3 p-Chloromethylphenylmalonic acid

When in the procedure of Example 1 (A) an equivalent amount ofphenylmalonic acid diethyl ester is substituted for phenylacetic acid,p-chloromethylphenylmalonic acid diethyl ester is obtained which yieldsthe corresponding acid upon acid hydrolysis. In a similar manner thechloromethyl derivatives listed in Table III may be prepared when thediethyl ester of the corresponding acid listed in Table III issubstituted for phenylmalonic acid diethyl ester.

                  TABLE III                                                       ______________________________________                                        Acid             Chloromethyl derivative                                      ______________________________________                                        2-sulfophenylacetic                                                                            2-sulfo-p-chloromethyl-                                      acid             phenylacetic acid                                            3-phenyl-2-sulfopro-                                                                           3-(p-chloromethyl-                                           pionic acid      phenyl)-2-sulfopro-                                                           pionic acid                                                  4-phenyl-2-sulfo-                                                                              4-(p-chloromethyl-                                           butyric acid     phenyl)-2-sulfobutyric                                                        acid                                                         benzylmalonic acid                                                                             p-chloromethylbenzyl-                                                         malonic acid                                                 phenethylmalonic p-chloromethylphen-                                          acid             ethylmalonic acid                                            2-phenoxyethyl-  2-(p-chloromethyl-                                           malonic acid     phenoxy)ethylmalonic                                                          acid                                                         2-phenylthioethyl-                                                                             2-(p-chloromethyl-                                           malonic acid     phenyl)thioethyl-                                                             malonic acid                                                 anilinomethyl-   p-chloromethylanilino-                                       malonic acid     methylmalonic acid                                           2-thienylmalonic 2-[2-(5-chloromethyl)-                                       acid             thienyl]malonic acid                                         2-thenylmalonic  2-[2-(5-chloromethyl)-                                       acid             thenyl]malonic acid                                          ______________________________________                                    

EXAMPLE 4 5-Chloromethyl-2-thienylacetyl chloride

2-Thiophenecarboxylic acid is treated in a solution of chloroform withchloromethyl ether in the presence of 0.9 to 2.2 equivalents of aluminumchloride to give 5-chloromethyl-2-thienylcarboxylic acid. Treatment ofthe obtained acid with excess thionyl chloride at room temperature forabout 16 hours yields the acid chloride which is reacted withdiazomethane to give the corresponding diazoketone. A methanol solutionof the diazoketone is irradiated under nitrogen for about one hour witha high pressure mercury lamp using a Quarz filter. The methyl5-chloromethyl-2-thienylacetate is obtained upon work up and columnchromatography on silica gel. The acetate is hydrolyzed by treatment ofa 1:1 mixture of acetic acid and concentrated hydrochloric acid at roomtemperature overnight to give 5-chloromethyl-2-thienylacetic acid.

When in the procedure of Example 1 (B) 5-chloromethyl-2-thienylaceticacid, is substituted for p-chloromethylphenyl acetic acid,5-chloromethyl-2-thienylacetyl chloride is obtained.

EXAMPLE 5 o-Hydroxymethylphenylacetic acid lactone

The neutral by-product obtained in Example 1 is purified by sublimationunder vacuum (0.05 mm Hg at 80° C) to give o-hydroxymethylphenylaceticacid lactone. M.P. 82° C.

EXAMPLE 6 o-Bromomethylphenylacetyl chloride

To a solution of 5 ml of glacial acetic acid saturated with hydrogenbromide gas is added at 0° C a solution of o-hydroxymethylphenylaceticacid lactone (0.55 g) in 2 ml of glacial acetic acid. The mixture isstirred at room temperature for two hours then refluxed for one hourduring which time hydrogen bromide gas is bubbled into the mixture. Theexcess lactone and solvent are removed under high vacuum at roomtemperature. The resulting oily residue is triturated three times withhexane to give o-bromomethylphenylacetic acid. M.P. 110° C.

A solution of 0.18 g of o-bromomethylphenylacetic acid in excess thionylchloride is stirred at room temperature for 18 hours after which theunreacted thionyl chloride is removed under high vacuum to giveo-bromomethylphenylacetyl chloride as an oily residue.

EXAMPLE 7 o-Chloromethyl-p-methoxymandelic acid chloride

A solution of 1.1 g of 2-chloromethyl-4-methoxymandelic acid, obtainedby the procedure described by B. Reichert et al., Pharmazie 5, 10(1950), in 25 ml of thionyl chloride is stirred at room temperature forabout 16 hours after which the excess thionyl chloride is removed underhigh vacuum to give o-chloromethyl-p-methoxymandelic acid chloride as anoil.

EXAMPLE 83-[(Acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylicacid propionyloxymethyl ester

To 35 ml of dimethyl formamide is added 7.5 g of the sodium salt of3-[(acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid, and the solution is stirred at room temperature for about 30minutes after which 8 ml of chloromethylpropionate is added. Stirring iscontinued at room temperature for about 3 hours. The mixture is dilutedwith ethyl acetate and washed with water. The organic layer is separatedand evaporated to dryness. The residue is recrystallized from ethylacetate to give3-[(acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid propionyloxymethyl ester.

In a similar manner when an appropriate amount of chloromethylpivalate,chloromethylacetate or chloromethylbutyrate is substituted forchloromethylpropionate, the following respective products are obtained:3-[(acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylicacid pivalyloxymethyl ester,3-[(acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylicacid acetyloxymethyl ester,3-[(acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid butyryloxymethyl ester.

EXAMPLE 93-[(Acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid 2-amino-3-methylbutyryloxymethyl ester

A suspension of 5 grams of3-[(acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid sodium salt and 8.5 grams of N-tert-butoxycarbonyl-L-valinechloromethyl ester, which is prepared by the general procedure describedin W. German Offen. 2,236,620, are mixed in 100 ml of dimethyl formamideand stirred for 72 hours. The mixture is diluted with ethyl acetate,washed with water with aqueous bicarbonate and again with water. Theorganic layer is dried over magnesium sulfate, filtered, and evaporatedto dryness to give3-[(acetyloxy)-methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0oct-2-ene-2-carboxylic acidN-tert-butoxycarbonyl-2-amino-3-methylbutyryloxymethyl ester from whichthe amine protecting group is removed by standard procedures to give thetitle product.

EXAMPLE 103-[(Acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylicacid N-ethoxycarbonyl-N-methylaminomethyl ester 725 mg (2.5 mM) of thesodium salt of3-[(acetyloxy)-methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid in 50 ml of dimethyl formamide is treated at room temperature with375 mg (2.5 mM) of N-chloromethyl-N-methylurethane for one hour. Themixture is carefully poured into ice water and the precipitated solid isremoved by filtration and washed with water. The solid is dissolved inethylacetate and washed with aqueous sodium bicarbonate and then withwater. The organic layer is dried over magnesium sulfate filtered andevaporated to dryness in vacuo to give3-[(acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid N-ethoxycarbonyl-N-methylaminomethyl ester.

When in the above procedure an appropriate amount ofN-methyl-N-propionylaminomethyl chloride, N:butyrylaminomethyl chloride,N-acetylaminomethyl chloride, or N-methylN-ethoxycarbonylaminomethylchloride is substituted for N-chloromethyl-N-methylurethane thefollowing respective compounds are obtained:

3-[(acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylicacid N-methyl-N-propionylaminomethyl ester,

3-[(acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylicacid N-butyrylaminomethyl ester,

3-[(acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylicacid N-acetylaminomethyl ester and,

3-[(acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylicacid N-methyl-N-ethoxycarbonylaminomethyl ester.

EXAMPLE 113-[(Acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylicacid p-pivalyloxybenzyl ester

To a suspension of 6.6 mM of3-[(acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid sodium salt in 35 ml of dimethyl formamide (DMF) is added 2equivalents of p=pivalyloxybenzyl alcohol followed by cooling to 0° Cafter which 7.2 mM of dicyclohexylcarbodiimide in 7.5 ml of DMF is addeddropwise with stirring. The mixture is stirred at 0° C for one hour andan additional four hours at room temperature. The formeddicyclohexylurea is removed by filtration. The filtrate is diluted withchloroform, washed with water, dried over magnesium sulfate, filtered,and evaporated in vacuo to give3-[(acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid p-pivalyloxybenzyl ester.

When in the above procedure an appropriate amount ofp-(propionyloxy)benzyl alcohol, p-(acetyloxy)benzyl alcohol, orp-(valeryloxy)benzyl alcohol is substituted for p-pivalyloxybenzylalcohol the following respective products are obtained:

3-[(acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylicacid p-(propionyloxy)benzyl ester,

3-[(acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylicacid p-(acetyloxy)benzyl ester, and

3-[(acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylicacid p-(valeryloxy)benzyl ester.

EXAMPLE 12 3-(2-Methyl-1,3,4-thiadiazol-5-ylthio)-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid

In about 1 liter of water is dissolved 0.1 mole of the sodium salt of3-[(acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid at 70° C under nitrogen atmosphere. To the solution is added 1equivalent of sodium bicarbonate and 2 equivalents of2-methyl-1,3,4-thiadiazol-5-ylthiol. The mixture is stirred at 70° C for3 hours after which the pH is adjusted to 3.5, and the resultingprecipitate collected giving3-(2-methyl-1,3,4-thiadiazol-5-ylthio)-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid.

When in the above procedure an equivalent amount of1,3,4-thiadiazol-5-ylthiol, 3-methyl-1,2,4-thiadiazol-5-ylthiol,tetrazol-5-ylthiol, 1-methyltetrazol-5-ylthiol or2-methyl-1,3,4-oxadiazol-5ylthiol is substituted for2-methyl-1,3,4-thiadiazol-5-ylthiol the following respective productsare obtained:

3-(1,3,4-thiadiazol-5-ylthio)-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid,3-(3-methyl-1,2,4-thiadiazol-5-ylthio)-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid,3-(tetrazol-5-ylthio)-7-amino-8-oxo-5thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylicacid,

3-(1-methyltetrazol-5-ylthio)-7-amino-8-oxo-5thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid, and

3-(2-methyl-1,3,4-oxadiazol-5-ylthio)-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid.

EXAMPLE 13

When in the procedure of Example 12 appropriate amounts of the sodiumsalt of the cephalosporin derivative and the heterocyclicthiolderivative listed below in Table IV are substituted respectively for thesodium salt of3-[(acetyloxy)methyl-]-7-amino-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylicacid and 2-methyl-1,3,4-thiadiazol-5-ylthiol the respective productslisted in Table IV are obtained.

                                      TABLE IV                                    __________________________________________________________________________    Cephalosporin Derivative  Heterocyclicthiol   Product                         __________________________________________________________________________    3-[(acetyloxy)methyl]-7-amino-8-oxo-                                                               3-methyl-1,2,4-thiadiazol-5-                                                                  3-(3-methyl-1,2,4-thiadiazol-5-          5-thia-1-azabicyclo[4.2.0]oct-2-ene-                                                               ylthiol         ylthio)-7-amino-8-oxo-5-thia-1-          2-carboxylic acid propionyloxymethyl azabicyclo[4.2.0]oct-2-ene-2-            ester                                carboxylic acid propionyloxy-                                                 methyl ester                             3-[(acetyloxy)methyl]-7-amino-8-oxo-                                                               1-methyltetrazol-5-ylthiol                                                                    3-(1-methyltetrazol-5-ylthio)-7-         5-thia-1-azabicyclo[4.2.0]oct-2-ene- amino-8-oxo-5-thia-1-azabicyclo-         2-carboxylic acid p-pivalyloxymethyl [4.2.0]oct-2-ene-2-carboxylic acid       ester                                pivalyloxymethyl ester                   3-[(acetyloxy)methyl]-7-amino-8-oxo-                                                               1,3,4-thiadiazol-5-ylthiol                                                                    3-(1,3,4-thiadiazol-5-ylthio)-7-         5-thia-1-azabicyclo[4.2.0]oct-2-ene- amino-8-oxo-5-thia-1-azabicyclo-         2-carboxylic acid acetyloxymethyl    [4.2.0]oct-2-ene-2-carboxylic acid       ester                                acetyloxymethyl ester                    3-[(acetyloxy)methyl]-7-amino-8-oxo-                                                               tetrazol-5-ylthiol                                                                            3-(tetrazol-5-ylthio)-7-amino-8-         5-thia-1-azabicyclo[4.2.0]oct-2-ene- oxo-5-thia-1-azabicyclo[4.2.0]oct-       2-carboxylic acid butyryloxymethyl   2-ene-2-carboxylic acid butyryloxy-      ester                                methyl ester                             3-[(acetyloxy)methyl]-7-amino-8-oxo-                                                               2-methyl-1,3,4-oxadiazol-                                                                     3-(2-methyl-1,3,4-oxadiazol-5-yl-        5-thia-1-azabicyclo[4.2.0]oct-2-ene-                                                               5-ylthiol       thio)-7-amino-8-oxo-5-thia-1-aza-        2-carboxylic acid 2-amino-3-methyl-  bicyclo[4.2.0]oct-2-ene-2-carboxylic                                          4                                        butyryloxymethyl ester               acid 2-amino-3-methylbutyryloxy-                                              methyl ester                             3-[(acetyloxy)methyl]-7-amino-8-oxo-                                                               2-methyl-1,3,4-thiadiazol-5-                                                                  3-(2-methyl-1,3,4-thiadiazol-5-yl-       5-thia-1-azabicyclo[4.2.0]oct-2-ene-                                                               ylthiol         thio)-7-amino-8-oxo-5-thia-1-aza-        2-carboxylic acid N-ethoxycarbonyl-  bicyclo[4.2.0]oct-2-ene-2-carboxylic                                          .                                        N-methylaminomethyl ester            acid N-ethoxycarbonyl-N-methylamino-                                          methyl ester                             3-[(acetyloxy)methyl]-7-amino-8-oxo-                                                               1-methyltetrazol-5-ylthiol                                                                    3-(1-methyltetrazol-5-ylthio)-7-         5-thia-1-azabicyclo[4.2.0]oct-2-ene- amino-8-oxo-5-thia-1-azabicyclo-         2-carboxylic acid p-pivalyloxybenzyl [4.2.0]oct-2-ene-2-carboxylic acid       ester                                p-pivalyloxybenzyl ester                 3-[(acetyloxy)methyl]-7-amino-7-                                                                   2-methyl-1,3,4-thiadiazol-                                                                    3-(2-methyl-1,3,4-thiadiazol-5-          methoxy-8-oxo-5-thia-1-azabicyclo-                                                                 5-ylthiol       ylthio)-7-amino-7-methoxy-8-oxo-         [4.2.0]oct-2-ene-2-carboxylic acid   5-thia-1-azabicyclo[4.2.0]oct-2-         (prepared by acid hydrolysis of the  ene-2-carboxylic acid                    corresponding benzhydryl ester                                                described in U.S. patent 3,778,432)                                           3-[(acetyloxy)methyl]-7-amino-8-oxo-                                                               1-methyltetrazol-5-ylthiol                                                                    3-(1-methyltetrazol-5-ylthio)-7-         5-thia-1-azabicyclo[4.2.0]oct-2-ene- amino-8-oxo-5-thia-1-azabicyclo-         2-carboxylic acid p-(propionyloxy)-  [4.2.0]oct-2-ene-2-carboxylic acid       benzyl ester                         p-(propionyloxy)benzyl ester             3-[(acetyloxy)methyl]-7-amino-8-oxo-                                                               tetrazol-5-ylthiol                                                                            3-(tetrazol-5-ylthio)-7-amino-8-         5-thia-1-azabicyclo[4.2.0]oct-2-ene- oxo-5-thia-1-azabicyclo[4.2.0]-          2-carboxylic acid p-(acetyloxy)benzyl                                                                              oct-2-ene-2-carboxylic acid              ester                                p-(acetyloxy)benzyl ester                3-[(acetyloxy)methyl]-7-amino-8-oxo-                                                               3-methyl-1,2,4-thiadiazol-5-                                                                  3-(3-methyl-1,2,4-thiadiazol-5-          5-thia-1-azabicyclo[4.2.0]oct-2-ene-                                                               ylthiol         ylthio)-7-amino-8-oxo-5-thia-1-          2-carboxylic acid p-(valeryloxy)benzyl                                                                             azabicyclo[4.2.0]oct-2-ene-2-carbox-     ester                                ylic acid p-(valeryloxy)benzyl           __________________________________________________________________________                                         ester                                

EXAMPLE 143-[Acetyloxy)methyl]-7-[[2-[4-(chloromethyl)phenyl]-acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

A mixture of 1 g of3-[(acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid and 1 g of p-chloromethylphenylacetyl chloride in 45 ml of ethylacetate is refluxed for about 2 hours after which the solvent is removedunder vacuum yielding a yellow-brown amorphous product which ischromatographed on silica gel using benzene-acetone as the eluant togive3-[(acetyloxy)methyl]-7-[[2-[4-(chloromethyl)phenyl]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid. M.P. 164°-165° C. (dec.).

In a similar manner when an appropriate amount of each of theacetyloxymethyl ester, the propionyloxybenzyl ester, the2-amino-3-methylbutyryloxymethyl ester, the pivalyloxymethyl ester, andthe N-ethoxycarbonyl-N-methylaminomethyl ester of3-[(acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid or3-(1-methyltetrazol-5-ylthio)-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid pivalyloxybenzylester,3-(2-methyl-1,3,4-thiadiazol-5-ylthio)-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid propionyloxymethyl ester or the corresponding pivalyloxymethylester or3-(2-methyl-1,3,4-thiadiazol-5-ylthio)-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid, or3-(1-methyltetrazol-5-ylthio)-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid is substituted for the free 7-aminocephalosporanic acid in theabove Example, the following compounds are obtained:

3-[(acetyloxy)methyl]-7-[[2-[4-(chloromethyl)phenyl]-acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid acetyloxymethyl ester,

3-[(acetyloxy)methyl]-7-[[2-[4-(chloromethyl)phenyl]-acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid propionyloxybenzyl ester,

3-[(acetyloxy)methyl]-7-[[2-[4-(chloromethyl)phenyl]-acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid 2-amino-3-methylbutyryloxymethyl ester,

3-[(acetyloxy)methyl]-7-[[2-[4-(chloromethyl)phenyl]-acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid pivalyloxymethyl ester,

3-[(acetyloxy)methyl]-7-[[2-[4-(chloromethyl)phenyl]-acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid N-ethoxycarbonyl-N-methylaminomethyl ester,

3-(1-methyltetrazol-5-ylthio)-7-[[2-[4-(chloromethyl)phenyl]-acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid pivalyloxybenzyl ester,

3-(2-methyl-1,3,4-thiadiazol-5-ylthio)-7-[[2-[4-(chloromethyl)phenyl]acetyl]amino]-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylicacid propionyloxymethyl ester,

3-(2-methyl-1,3,4-thiadiazol-5-ylthio)-7-[[2-[4-(chloromethyl)phenyl]acetyl]amino]-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylicacid pivalyloxymethyl ester,

3-(2-methyl-1,3,4-thiadiazol-5-ylthio)-7-[[2-[4-(chloromethyl)phenyl]acetyl]amino]-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylicacid, and

3-(1-methyltetrazol-5-ylthio)-7-[[2-[4-(chloromethyl)-phenyl]acetyl]amino]-8-oxo-5-thia-1azabicyclo[4.2.0]-oct-2-ene-2-carboxylicacid.

EXAMPLE 157-[[2-[4-(Chloromethyl)phenyl]acetyl]amino]-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2carboxylicacid

By the procedure of Example 14, only substituting 1 g of7-amino-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid for3-acetyloxymethyl-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid,7-[[2-[4-(chloromethyl)phenyl]acetyl]amino]-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid is obtained. M.P. 145°-146° C.

EXAMPLE 166-[[2-[4-(Chloromethyl)phenyl]acetyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid

When in Example 14 an appropriate amount of the triethylamine salt of6-amino-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid is substituted for3-[(acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ene-2-carboxylicacid,6-[[2-[4-(chloromethyl)phenyl]-acetyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid is obtained.

EXAMPLE 173-[(Acetyloxy)methyl]-7-[[2-[4-(chloromethyl)phenyl]-2-aminoacetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

p-Chloromethylphenylglycine wherein the amino group is protected withtert-butoxycarbonyl, is treated with isobutyl chloroformate in thepresence of triethylamine. The thus obtained mixed anhydride is reactedwith the triethylamine salt of3-[(acetyloxy)methyl]-7-amino-8-oxo-5-thio-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid at 0° C for about 4 hours. The resulting product is isolated, andthe amine protecting group is removed by acid hydrolysis to give,3-[(acetyloxy)methyl]-7-[[2-[4-(chloromethyl)phenyl]-2-aminoacetyl]amino]-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylicacid.

When in the above procedure an appropriate amount of the triethylaminesalt of3-(2-methyl-1,3,4-thiadiazol-5-ylthio)-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid or3-(1-methyltetrazol-5-ylthio)-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid,3-[(acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid pivalyloxymethyl ester is substituted for the triethylamine salt of3-[(acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ene-2-carboxylicacid the following respective products are obtained:

3-(2-methyl-1,3,4-thiadiazol-5-ylthio)-7-[[2-[4-(chloromethyl)phenyl]-2-aminoacetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid,

3-(1-methyltetrazol-5-ylthio)-7-[[2-[4-(chloromethyl)-phenyl]-2-aminoacetyl]amino]-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylicacid,

3-[(acetyloxy)methyl]-7-[[2-[4-(chloromethyl)phenyl]-2-aminoacetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid pivalyloxymethyl ester.

EXAMPLE 186-[[2-[4-(Chloromethyl)phenyl]-2-aminoacetyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid

When in the procedure of Example 17 an appropriate amount of thetriethylamine salt of6-amino-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid is substituted for the triethylamine salt of3-[(acetyloxy)-methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid,6-[[2-[4-(chloromethyl)phenyl]-2-aminoacetyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid is obtained.

EXAMPLE 193-[(Acetyloxy)methyl]-7-[[2-[2-(chloromethyl)-4-methoxyphenyl]-2-hydroxyacetyl]amino]-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylicacid

A mixture of 1 g of3-[(acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid and 1.2 g of 2-chloromethyl-4-methoxymandelic acid chloride in 200ml of ethyl acetate is refluxed for 50 minutes after which the solventis removed under high vacuum. The resulting product is chromatographedon silica gel using benzene-acetone as the eluant. The product obtainedis triturated with ether to give3-[(acetyloxy)methyl]-7-[[2-[2-(chloromethyl)-4-methoxyphenyl]-2-hydroxyacetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid. M.P. 140°-142° C (dec.).

When in the above procedure an appropriate amount of3-(2-methyl-1,3,4-thiadiazol-5-ylthio)-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid or3-(1-methyltetrazol-5-ylthio)-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid is substituted for the corresponding 3-[(acetoxy)methyl] derivativeand 2-(p-chloromethylphenyl)mandelic acid chloride is substituted for2-chloromethyl-4-methoxymandelic acid,3-(2-methyl-1,3,4-thiadiazol-5-ylthio]-7-[[2-[4-(chloromethyl)-phenyl]-2-hydroxyacetyl]amino]-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylicacid and3-(1-methyltetrazol-5-ylthio)-7-[[2-[4-(chloromethyl)phenyl]-2-hydroxyacetyl]-amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid are obtained.

EXAMPLE 206-[[2-[2-(Chloromethyl)-4-methoxyphenyl]-2-hydroxyacetyl]-amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]-heptane-2-carboxylicacid

When in Example 19 an appropriate amount of the triethylamine salt of6-amino-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid is substituted for3-[(acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ene-2-carboxylicacid,6-[[2-[2-(chloromethyl)-4-methoxyphenyl]-2-hydroxyacetyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid is obtained.

EXAMPLE 21 3-[(Acetyloxy-7-[[2-[5-(chloromethyl)-2-thienyl]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-carboxylicacid

A mixture of 1.2 equivalents of 5-chloromethyl-2-thienylacetyl chlorideand 1 equivalent of3-[(acetyloxy)-methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid is refluxed for 50 minutes in ethyl acetate after which the solventis removed and the remaining product is purified by columnchromatography on silica gel to give3-[(acetyloxy)methyl]-7-[[2-[5-(chloromethyl)-2-thienyl]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid.

EXAMPLE 223-[(Acetyloxy)methyl]-7-[[2-[4-(chloromethyl)phenyl]-2-carboxyacetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ene-2-carboxylicacid

α-Carboxy-p-chloromethylphenylacetyl nitrophenyl polymer, preparedaccording to the procedure described in Canadian Patent No. 892,580,carrying 4 m. mole of p-chloromethylphenylmalonic acid is suspended forabout 8 hours in 20 ml of dry methylene chloride solution containing 1m. mole of3-[(acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid triethylammonium salt, which is prepared from 544 mg of7-aminocephalosporanic acid (1 m. mole) and 0.56 ml of triethylamine (1m. mole) at room temperature. After only traces of7-aminocephalosporanic acid remain in solution, which is determined bythin layer chromatography on cellulose in 70% aqueous propanol, thepolymer is filtered off and washed with 3 portions of 50 ml each ofmethylene chloride. The combined filtrates are evaporated and theresidue is dissolved in 20 ml or distilled water. This solution isacidified to pH 2 by adding 0.2N hydrochloric acid and extracted twicewith ethyl acetate. The organic solution is dried over sodium sulfateand evaporated at room temperature. The remaining solid is driedovernight over phosphorus pentoxide under vacuum to give3-[(acetyloxy)-methyl]-7-[[2-[4-(chloromethyl)phenyl]-2-carboxyacetyl]-amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid.

When in the above procedure an appropriate amount of3-(2-methyl-1,3,4-thiadiazol-5-ylthio)-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid,3-[(acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid pivalyloxymethyl ester, or3-(1-methyltetrazol-5-ylthio)-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid pivalyloxybenzyl ester is substituted for3-[(acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid the following products are obtained:

3-(2-methyl-1,3,4-thiadiazol-5-ylthio)-7-[[2-[4-(chloromethyl)phenyl]-2-carboxyacetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid,

3-[(acetyloxy)methyl]-7-[[2-[4-(chloromethylphenyl]-2-carboxyacetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ene-2-carboxylicacid pivalyloxymethyl ester, and3-(1-methyltetrazol-5-ylthio)-7-[[2-[4-(chloromethyl)phenyl]-2-carboxyacetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid pivalyloxybenzyl ester.

EXAMPLE 23

When in the procedure of Example 14 an appropriate amount of an acidchloride listed in Table V is substituted for p-chloromethylphenylacetylchloride the respective cephalosporin derivatives listed in Table V areobtained.

                                      TABLE V                                     __________________________________________________________________________             Acid Chloride            Cephalosporin Derivative                    __________________________________________________________________________    p-chloromethylhydrotropic acid chloride                                                                   3-[(acetyloxy)methyl]-7-[[2-[4-(chloromethyl)-                                phenyl]-2-methylacetyl]amino]-8-oxo-5-thia-1-                                 azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid      p-chloromethyldihydrocinnamic acid chloride                                                               3-[(acetyloxy)methyl]-7-[[3-[4-(chloromethyl)-                                phenyl]propionyl]amino]-8-oxo-5-thia-1-azabi-                                 cyclo[4.2.0]oct-2-ene-2-carboxylic acid           p-chloromethyl-2-methylhydrocinnamic acid                                                                 3-[(acetyloxy)methyl]-7-[[3-[4-(chloromethyl)-    chloride                    phenyl]-2-methylpropionyl]amino]-8-oxo-5-thia-                                1-                                                                            azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid      2-methyl-4-(p-chloromethylphenyl)butyric-                                                                 3-[(acetyloxy)methyl]-7-[[4-[4-(chloromethyl)     acid chloride               phenyl]-2-methylbutyryl]amino]-8-oxo-5-thia-1-                                azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid      p-chloromethylphenoxyacetic acid chloride                                                                 3-[(acetyloxy)methyl]-7-[[2-[4-(chloromethyl)-                                phenoxy]acetyl]amino]-8-oxo-5-thia-1-azabicycl                                o-                                                                            [4.2.0]oct-2-ene-2-carboxylic acid                2-(p-chloromethylphenoxy)propionic acid                                                                   3-[(acetyloxy)methyl]-7-[[2-[4-(chloromethyl)-    chloride                    phenoxy]2-methylacetyl]amino]-8-oxo-5-thia-1-                                 azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid      2-methyl-4-(p-chloromethylphenoxy)butyric                                                                 3-[(acetyloxy)methyl]-7-[[4-[4-(chloromethyl)-    acid chloride               phenoxy]-2-methylbutyryl]amino]-8-oxo-5-thia-1                                -                                                                             azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid      p-chloromethylanilinoacetic acid chloride                                                                 3-[(acetyloxy)methyl]-7-[[2-[4-(chloromethyl)-                                anilino]acetyl]amino]-8-oxo-5-thia-1-azabicycl                                o-                                                                            [4.2.0]oct-2-ene-2-carboxylic acid                3-(p-chloromethylanilino)butyric                                                                          3-[(acetyloxy)methyl]-7-[[3-[4-(chloromethyl)-    acid chloride               anilino]-2-methylpropionyl]amino]-8-oxo-5-thia                                -                                                                             1-azabicyclo[4.2.0] oct-2-ene-2-carboxylic                                    acid                                              p-chloromethylphenylthioacetic acid chloride                                                              3-[(acetyloxy)methyl]-7-[[2-[4-(chloromethyl)-                                phenylthio]acetyl]amino]-8-oxo-5-thia-1-azabi-                                cyclo[4.2.0]oct-2-ene-2-carboxylic acid           o-chloro-p-chloromethylphenylacetic acid                                                                  3-[(acetyloxy)methyl]-7-[[2-[2-(chloro)-4-        chloride                    (chloromethyl)phenyl]acetyl]amino]-8-oxo-5-                                   thia-1-azabicyclo[4.2.0]oct-2-ene-2-carbox-                                   ylic acid                                         4-(p-chloromethylphenyl)thiobutyric acid                                                                  3-[(acetyloxy)methyl]-7-[[4-[4-(chloromethyl)-    chloride                    phenylthio]butyryl]amino]-8-oxo-5-thia-1-aza-                                 bicyclo[4.2.0]oct-2-ene-2-carboxylic              __________________________________________________________________________                                acid                                          

In a similar manner as described in Example 14 when an appropriateamount of the triethylamine salt of6-amino-3,3-dimethyl-7-oxo-4-thia-1-azabycyclo[3.2.0]heptane-2-carboxylicacid is reacted with an appropriate amount of the acid chlorides listedin Table V the following respective penicillin derivatives are obtained.

6-[[2-[4-(chloromethyl)phenyl]-2-methylacetyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid,

6-[[3-[4-(chloromethyl)phenyl]propionyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid,

6-[[3-[4(chloromethyl)phenyl]-2-methylpropionyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid,

6-[[4-[4-(chloromethyl)phenyl]-2-methylbutyryl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid,

6-[[2-[4-(chloromethyl)phenoxy]acetyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid,

6-[[2-[4-(chloromethyl)phenoxy]-2-methylacetyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid,

6-[[4-[4-(chloromethyl)phenoxy]-2-methylbutyryl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid,

6-[[2-[4-(chloromethyl)anilino]acetyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid,

6-[[3-[4-(chloromethyl)anilino]-2-methylpropionyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid,

6-[[2-[4-(chloromethyl)phenylthio]acetyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid,

6-[[2-[2-(chloro)-4-(chloromethyl)phenyl]acetyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid,

6-[[4-[4-(chloromethyl)phenylthio]butyryl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid.

EXAMPLE 24

When in the procedure of Example 17 an appropriate amount of an acidlisted in the following Table VI is substituted forp-chloromethylphenylglycine the respective cephalosporin derivativeslisted in Table VI are obtained:

                                      TABLE VI                                    __________________________________________________________________________             Acid                Cephalosporin Derivative                         __________________________________________________________________________    p-(chloromethylphenyl)alanine                                                                      3-[(acetyloxy)methyl]-7-[[3-[4-(chloromethyl)-                                phenyl]-2-aminopropionyl]amino]-8-oxo-5-thia-1-                               azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid             2-amino-4-(p-chloromethylphenoxy)-                                                                 3-[(acetyloxy)methyl]-7-[[4-[4-(chloromethyl)-           butyric acid         phenoxy]-2-aminobutyryl]amino]-8-oxo-5-thia-1-                                azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid             2-amino-4-(p-chloromethylanilino)-                                                                 3-[(acetyloxy)methyl]-7-[[4-[4-(chloromethyl)ani-        butyric acid         lino]-2-aminobutyryl]amino]-8-oxo-5-thia-1-aza-                               bicyclo[4.2.0]oct-2-ene-2-carboxylic acid                3-(p-chloromethylphenyl)thioalanine                                                                3-[(acetyloxy)methyl]-7-[[3-[4-(chloromethyl)-                                phenylthio]-2-aminopropionyl]amino]-8-oxo-5-                                  thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic                                acid                                                     2-[2-(5-chloromethyl)thienyl]glycine                                                               3-[(acetyloxy)methyl]-7-[[2-[5-(chloromethyl)-2-                              thienyl]-2-aminoacetyl]amino]-8-oxo-5-thia-1-                                 azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid             2-amino-4-[2-(5-chloromethyl)thienyl]-                                                             3-[(acetyloxy)methyl]-7-[[4-[5-(chloromethyl)-2-         butyric acid         thienyl]-2-aminobutyryl]amino]-8-oxo-5-thia-1-                                azabicyclo[4.2.0]oct-2-ene-2-carboxylic                  __________________________________________________________________________                         acid                                                 

In a similar manner as described in Example 17 when an appropriateamount of6-amino-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid is reacted with an appropriate amount of the acids listed in TableVI the following respective penicillin derivatives are obtained.

6-[[3-[4-chloromethyl)phenyl]-2-aminopropionyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid,

6-[[4-[4-(chloromethyl]phenoxy]-2-aminobutyryl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid,

6-[[4-[4-(chloromethyl]anilino]-2-aminobutyryl]amino-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid,

6-[[3-[4-(chloromethyl]-2-aminopropionyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid,

6-[[2-[5-(chloromethyl)-2-thienyl]-2-aminoacetyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid,

6-[[4-[5-(chloromethyl)-2-thienyl]-2-aminobutyryl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid,

EXAMPLE 25

When in the procedure of Example 19 an appropriate amount of an acidchloride listed in the following Table VII is substituted for2-chloromethyl-4-methoxymandelic acic chloride the respectivecephalosporin derivatives listed in Table VII are obtained:

                                      TABLE VI                                    __________________________________________________________________________           Acid Chloride         Cephalosporin Derivative                         __________________________________________________________________________    3-(p-chloromethylphenyl)lactic acid chloride                                                         3-[(acetyloxy)methyl]-7-[[3-[4-(chloromethyl)-                                phenyl]-2-hydroxypropionyl]amino]-8-oxo-5-thia-                               1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid         2-hydroxy-4-(p-chloromethylphenyl)butyric                                                            3-[(acetyloxy)methyl]-7-[[4-[4-(chloromethyl)-         acid chloride          phenyl]-2-hydroxybutyryl]amino]-8-oxo-5-thia-                                 1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid         2-hydroxy-2-[2-(5-chloromethyl)thienyl]-                                                             3-[(acetyloxy)methyl]-7-[[2-[5-(chloromethyl)-         acetic acid chloride   2-thienyl]-2-hydroxyacetyl]amino]-8-oxo-5-thia-                               1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid         p-chloromethylmandelic acid chloride                                                                 3-[(acetyloxy)methyl]-7-[[2-[4-(chloromethyl)-                                phenyl]-2-hydroxyacetyl]amino]-8-oxo-5-thia-1-                                azabicyclo[4.2.0]oct-2-ene-2-carboxylic                __________________________________________________________________________                           acid                                               

In a similar manner as described in Example 19 when an appropriateamount of6-amino-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid is reacted with an appropriate amount of the acid chlorides listedin Table VII the following respective penicillin derivatives areobtained:

6-[[3-[4-(chloromethyl)phenyl]-2-hydroxypropionyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid,

6-[[4-[4-(chloromethyl)phenyl]-2-hydroxybutyryl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid,

6-[[2-[5-(chloromethyl)-2-thienyl]-2-hydroxyacetyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3,2.0]heptane-2-carboxylicacid,

EXAMPLE 26

When in the procedure of Example 22 an appropriate amountof of an acidlisted in Table VIII is substituted for p-chloromethylphenylmalonic acidthe respective cephalosporin derivatives listed in Table VIII areobtained:

                                      TABLE VIII                                  __________________________________________________________________________              Acid                Cephalosporin Derivative                        __________________________________________________________________________    2-sulfo-p-chloromethylphenylacetic acid                                                               3-[(acetyloxy)methyl]-7-[[2-[4-(chloromethyl)-                                phenyl]-2-sulfoacetyl]amino]-8-oxo-5-thia-1-                                  azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid          4-(p-chloromethylphenyl)-2-sulfobutyric                                                               3-[(acetyloxy)methyl]-7-[[4-[4-(chloromethyl)-        acid                    phenyl]-2-sulfobutyryl]amino]-8-oxo-5-thia-1-                                 azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid          p-chloromethylbenzylmalonic acid                                                                      3-[(acetyloxy)methyl]-7-[[3-[4-(chloromethyl)-                                phenyl]-2-carboxypropionyl]amino]-8-oxo-5-thia-                               1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid        2-(p-chloromethylphenoxy)ethylmalonic acid                                                            3-[(acetyloxy)methyl]-7-[[4-[4-(chloromethyl)-                                phenoxy]-2-carboxybutyryl]amino]-8-oxo-5-thia-                                1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid        2-(p-chloromethylphenyl)thioethylmalonic acid                                                         3-[(acetyloxy)methyl]-7-[[4-[4-(chloromethyl)-                                phenylthio]-2-carboxybutyryl]amino]-8-oxo-5-thia-                             1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid        p-chloromethylanilinomethylmalonic acid                                                               3-[(acetyloxy)methyl]-7-[[3-[4-(chloromethyl)-                                anilino]-2-carboxypropionyl]amino]-8-oxo-5-thia-                              1-azabicyclo[ 4.2.0]oct-2-ene-2-carboxylic acid       2-[2-(5-chloromethyl)thenyl]malonic acid                                                              3-[(acetyloxy)methyl]-7-[[3-[5-(chloromethyl)-2-                              thienyl]-2-carboxypropionyl]amino]-8-oxo-5-thia-                              1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic             __________________________________________________________________________                            acid                                              

In a similar manner as described in Example 22 when an appropriateamount of6-amino-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid is reacted with the acids listed in Table VIII the followingrespective penicillin derivatives are obtained:

6-[[2-[4-(chloromethyl)phenyl]-2-sulfoacetyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3,2,0]heptane-2-carboxylicacid,

6-[[4-[4-(chloromethyl)phenyl]-2-sulfobutyryl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid,

6-[[3-[4-(chloromethyl)phenyl]-2-carboxypropionyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid,

6-[[4-[4-(chloromethyl)phenyl]-2-carboxybutyryl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid,

6-[[4-[4-(chloromethyl)phenylthio]-2-carboxybutyryl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid,

6-[[3-[4-(chloromethyl)anilino]-2-carboxypropionyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid, and

6-[[3-[5-(chloromethyl)-2-thienyl]-2-carboxypropionyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid.

EXAMPLE 273-[(Acetyloxy)methyl]-7-[[2-[4-(isothioureamethyl)phenyl]-acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid hydrochloride

A warm solution of 0.12 g of3-[(acetyloxy)methyl]-7-[[2-[4-(chloromethyl)phenyl]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid and 0.12 g of isothiourea in 30 ml of ethanol is refluxed for 4hours after which the solvent is removed under high vacuum at roomtemperature yielding an oil which is triturated with 80 ml ofbenzene-acetone (2:1) to give3-[(acetyloxy)methyl]-7-[[2-[4-(isothioureamethyl)phenyl]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid hydrochloride.

In a similar manner when the halomethylated derivatives and theisothiourea derivatives listed in the following Table IX are reacted therespective products listed in Table IX are obtained.

                                      TABLE IX                                    __________________________________________________________________________    Halomethylated Derivative                                                                           Isothiourea Derivative                                                                        Product                                 __________________________________________________________________________    3-[(acetyloxy)methyl]-7-[[2-[4-                                                                     isothiourea  3-[(acetyloxy)methyl]-7-[[2-[4-(iso-       (chloromethyl)phenyl]acetyl]amino]-                                                                              thioureamethyl)phenyl]acetyl]amino]-       8-oxo-5-thia-1-azabicyclo[4.2.0]-  8-oxo-5-thia-1-azabicyclo[4.2.0]-          oct-2-ene-2-carboxylic acid acetyl-                                                                              oct-2-ene-2-carboxylic acid acetyl-        oxymethyl ester                    oxymethyl ester                            3-[(acetyloxy)methyl]-7-[[2-[4-                                                                     isothiourea  3-[(acetyloxy)methyl]-7-[[2-[4-(iso-       (chloromethyl)phenyl]acetyl]amino]-                                                                              thioureamethyl)phenyl]acetyl]amino]-       8-oxo-5-thia-1-azabicyclo[4.2.0]-  8-oxo-5-thia-1-azabicyclo[4.2.0]-          oct-2-ene-2-carboxylic acid pro-   oct-2-ene-2-carboxylic acid pro-           pionyloxymethyl ester              pionyloxymethyl ester                      3-[(acetyloxy)methyl]-7-[[2-[4-                                                                     1,1,3-triethyl-                                                                            3-[(acetyloxy)methyl]-7-[[2-[4-(1,1,3-     (chloromethyl)phenyl]acetyl]amino]-                                                                 isothiourea  triethylisothioureamethyl)phenyl]-         8-oxo-5-thia-1-azabicyclo[4.2.0]-  acetyl]amino]-8-oxo-5-thia-1-azabi-        oct-2-ene-2-carboxylic acid butyryl-                                                                             cyclo[4.2.0]-oct-2-ene-2-carboxylic        oxymethyl ester                    acid butyryloxymethyl ester                3-[(acetyloxy)methyl]-7-[[2-[4-                                                                     isothiourea  3-[(acetyloxy)methyl]-7-[[2-[4-(iso-       (chloromethyl)phenyl]acetyl]amino]-                                                                              thioureamethyl)phenyl]acetyl]amino]-       8-oxo-5-thia-1-azabicyclo[4.2.0]-  8-oxo-5-thia-1-azabicyclo[4.2.0]-          oct-2-ene-2-carboxylic acid pival- oct-2-ene-2-carboxylic acid pival-         yloxymethyl ester                  yloxymethyl ester                          3-(2-methyl-1,3,4-thiadiazol-5-yl-                                                                  isothiourea  3-(2-methyl-1,3,4-thiadiazol-5-yl-         thio)-7-[[2-[4-(chloromethyl)phenyl]-                                                                            thio)-7-[[2-[4-(isothioureamethyl)-        acetyl]amino]-8-oxo-5-thia-1-azibi-                                                                              phenyl]acetyl]amino] -8-oxo-5-thia-1-      cyclo[4.2.0]oct-2-ene-2-carboxylic azabicyclo[4.2.0]oct-2-ene-2-carbox-       acid propionyloxymethyl ester      ylic acid propionyloxymethyl ester         3-(2-methyl-1,3,4-thiadiazol-5-yl-                                                                  isothiourea  3-(2-methyl-1,3,4-thiadiazol-5-yl-         thio)-7-[[2-[4-(chloromethyl)phenyl)-                                                                            thio)-7-[[2-[4-(isothioureamethyl)-        acetyl]amino]-8-oxo-5-thia-1-azabi-                                                                              phenyl)acetyl]amino]-8-oxo-5-thia-1-       cyclo[4.2.0]oct-2-ene-2-carboxylic azabicyclo[4.2.0]oct-2-ene-2-carbox-       acid pivalyloxymethyl ester        ylic acid pivalyloxymethyl ester           3-(1-methyltetrazol-5-ylthio)-7-[[2-                                                                n-propylisothiourea                                                                        3-(1-methyltetrazol-5-ylthio)-7-[[2-[4-    [4-(chloromethyl)phenyl]acetyl]amino]-                                                                           (n-propylisothioureamethyl)phenyl]acety                                       l]-                                        8-oxo-5-thia-1-azabicyclo[4.2.0]-  amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]                                       -                                          oct-2-ene-2-carboxylic acid        oct-2-ene-2-carboxylic acid                6-[[2-[4-(chloromethyl)phenyl]-                                                                     1-ethyl-3-n-propyliso-                                                                     6-[[2-[4-(1-ethyl-3-n-propylisothio-       acetyl]amino]-3,3-dimethyl-7-oxo-                                                                   thiourea     ureamethyl)phenyl]acetyl]amino]-3,3-       4-thia-1-azabicyclo[3.2.0]-        dimethyl)-7-oxo-4-thia-1-azabicyclo-       heptane-2-carboxylic acid          [3.2.0]heptane-2-carboxylic acid           3-[(acetyloxy)methyl]-7-[[2-[2-                                                                     isothiourea  3-[(acetyloxy)methyl]-7-[[2-[2-iso-        (chloromethyl)-4-methoxyphenyl]-   thioureamethyl)-4-methoxyphenyl)-2-        2-hydroxyacetyl]amino]-8-oxo-5-    hydroxyacetyl]amino]-8-oxo-5-thia-1-       thia-1-azabicyclo[4.2.0]oct-2-     azabicyclo[4.2.0]oct-2-ene-2-carbox-       ene-2-carboxylic acid              ylic acid                                  6-[[2-[2-(chloromethyl)-4-methoxy-                                                                  isothiourea  6-[[2-[2-(isothioureamethyl]-4-meth-       phenyl]-2-hydroxyacetyl]amino]-    oxyphenyl]-2-hydroxyacetyl]amino]-         3,3-dimethyl-7-oxo-4-thia-1-azabi- 3,3-dimethyl-7-oxo-4-thia-1-azabi-         cyclo[3.2.0]heptane-2-carboxylic   cyclo[ 3.2.0]heptane-2-carboxylic          acid                               acid                                       3-[(acetyloxy)methyl]-7-[[2-[5-                                                                     isothiourea  3-[(acetyloxy)methyl]-7-[[2-[5-iso-        (chloromethyl)-2-thienyl]acetyl)-  thioureamethyl)-2-thienyl]acetyl]-         amino]-8-oxo-5-thia-1-azabicyclo-  amino]-8-oxo-5-thia-1-azabicyclo-          [4.2.0]oct-2-ene-2-carboxylic      [4.2.0]oct-2-ene-2-carboxylic acid         acid                                                                          3-[(acetyloxy)methyl]-7-[[2-[4-                                                                     isothiourea  3-[(acetoxy)methyl]-7-[[2-[4-iso-          (chloromethyl)phenyl]-2-carboxy-   thioureamethyl)phenyl]-2-carboxy-          acetyl]amino]-8-oxo-5-thia-1-      acetyl]amino]-8-oxo-5-thia-1-azabi-        azabicyclo[4.2.0]oct-2-ene-2-      cyclo[4.2.0]oct-2-ene-2-carboxylic         carboxylic acid                    acid                                       3-[acetyloxy)methyl]-7-[[2-[4-                                                                      1,1-diethyl-3-                                                                             3-[(acetyloxy)methyl]-7-[[2-[4-(1,1-       (chloromethyl)phenyl]-2-methyl-                                                                     methylisothiourea                                                                          diethyl-3-methylisothioureamethyl)-        acetyl]amino]-8-oxo-5-thia-1-      phenyl]-2-methylacetyl]amino]-8-oxo-       azabyciclo[4.2.0]oct-2-ene-2-      5-thia-1-azabicyclo[4.2.0]oct-2-ene-       carboxylic acid                    2-carboxylic acid                          3-[(acetyloxy)methyl]-7-[[3-[4-                                                                     1-ethyl-3-methyl                                                                           3-[(acetyloxy)methyl]-7-[[3-[4-(1-         (chloromethyl)phenyl]propionyl]-                                                                    isothiourea  ethyl-3-methylisothioureamethyl)-          amino]-8-oxo-5-thia-1-azabicyclo-  phenyl]propionyl]amino]-8-oxo-5-thia-      [4.2.0]oct-2-ene-2-carboxylic      1-azabicyclo[4.2.0]oct-2-ene-2-car-        acid                               boxylic acid                               3-[(acetyloxy)methyl]-7-[[3-[4-                                                                     isothiourea  3-[(acetyloxy)methyl]-7-[[3-[4-(iso-       (chloromethyl)phenyl]-2-methylpro- thioureamethyl)phenyl]-2-methylpro-        pionyl]amino]-8-oxo-5-thia-1-      pionyl]amino]-8-oxo-5-thia-1-azabi-        azabicyclo[4.2.0]oct-2-ene-2-      cyclo[4.2.0]oct-2-ene-2-carboxylic         carboxylic acid                    acid                                       3-[(acetyloxy)methyl]-7-[[2-[4-                                                                     isothiourea  3-[(acetyloxy)methyl]  -7-[[2-[4-iso-      (chloromethyl)phenyl]acetyl]amino]-                                                                              thioureamethyl)phenyl]acetyl]amino]-       8-oxo-5-thia-1-azabicyclo[4.2.0]-  8-oxo-5-thia-1-azabicyclo[4.2.0]oct-       oct-2-ene-2-carboxylic acid acetyl-                                                                              2-ene-2-carboxylic acid acetyloxy-         oxymethyl ester                    methyl ester                               3-[(acetyloxy)methyl]-7-[[2-[4-                                                                     isothiourea  3-[(acetyloxy)methyl]-7-[[2-[4-(iso-       (chloromethyl)phenoxy]acetyl]amino]-                                                                             thioureamethyl)phenoxy]acetyl]amino]-      8-oxo-5-thia-1-azabicyclo[4.2.0]-  8-oxo-5-thia-1-azabicyclo[4.2.0]oct-       oct-2-ene-2-carboxylic acid        2-ene-2-carboxylic acid                    3-[(acetyloxy)methyl]-7-[[2-[4-                                                                     1-n-butyl-3-methyl-                                                                        3-[(acetyloxy)methyl]-7-[[2-[4-(1-n-       (chloromethyl)phenoxy]2-methyl-                                                                     isothiourea  butyl-3-methylisothioureamethyl)-          acetyl]amino]-8-oxo-5-thia-1-aza-  phenoxy]2-methylacetyl]amino]-8-oxo-       bicyclo[4.2.0]oct-2-ene-2-carbox-  5-thia-1-azabicyclo[4.2.0]oct-2-ene-       ylic acid                          2-carboxylic acid                          3-[(acetyloxy)methyl]-7-[ [2-[4-                                                                    1,3-di-n-propyl-                                                                           3-[(acetyloxy)methyl]-7-[[2-[4-(1,3-       (chloromethyl)phenyl]acetyl]amino]-                                                                 isothiourea  di-n-propylisothioureamethyl)phenyl]-      8-oxo-5-thia-1-azabicyclo[4.2.0]-  acetyl]amino]-8-oxo-5-thia-1-azabicyclo                                       -                                          oct-2-ene-2-carboxylic acid pro-   [4.2.0]oct-2-ene-2-carboxylic acid                                            pro-                                       pionyloxybenzyl ester              pionyloxybenzyl ester                      3-[(acetyloxy)methyl]-7-[[2-[4-                                                                     1,3-diisopropyl-                                                                           3-[(acetyloxy)methyl]-7-[[2-[4-(1,3-       (chloromethyl)anilino]acetyl]-                                                                      isothiourea  diisopropylisothioureamethyl)anilino]-     amino]-8-oxo-5-thia-1-azabicyclo-  acetyl]amino]-8-oxo-5-thia-1-azabicy-      [4.2.0]oct-2-ene-2-carboxylic      clo[4.2.0]oct-2-ene-2-carboxylic acid      acid                                                                          3-[(acetyloxy)methyl]-7-[[3-[4-                                                                     isothiourea  3-[(acetyloxy)methyl]-7-[[3-[4-(iso-       (chloromethyl)anilino]-2-methyl-   thioureamethyl)anilino]-2-methyl-          propionyl]amino]-8-oxo-5-thia-1-   propionyl]amino]-8-oxo-5-thia-1-           azabicyclo[4.2.0]oct-2-ene-2-      azabicyclo[4.2.0]oct-2-ene-2-              carboxylic acid                    carboxylic acid                            3-[(acetyloxy)methyl]-7-[[2-[4-                                                                     isothiourea  3-[(acetyloxy)methyl]-7-[[2-[4-(iso-       (chloromethyl)phenylthio]acetyl]-  thioureamethyl)phenylthio]acetyl]-         amino]-8-oxo-5-thia-1-azabicyclo-  amino]-8-oxo-5-thia-1-azabicyclo-          [4.2.0]oct-2-ene-2-carboxylic      [4.2.0]oct-2-ene-2-carboxylic acid         acid                                                                          3-[(acetyloxy)methyl]-7-[[2-[2-                                                                     isothiourea  3-[(acetyloxy)methyl]-7-[[2-[2-(chloro)                                       -                                          (chloro)-4-(chloromethyl)phenyl]-  4-(isothioureamethyl)phenyl]acetyl]amin                                       o]-                                        acetyl]amino]-8-oxo-5-thia-1-aza-  8-oxo-5-thia-1-azabicyclo[4.2.0]-          bicyclo[4.2.0]oct-2-ene-2-         oct-2-ene-2-carboxylic acid                carboxylic acid                                                               3-[(acetyloxy)methyl]-7-[[4-[4-                                                                     3-n-propyliso-                                                                             3-[(acetyloxy)methyl]-7-[[4-[4-(3-n-       (chloromethyl)phenylthio]butyryl]-                                                                  thiourea     propylisothioureamethyl)phenylthio]-       amino]-8-oxo-5-thia-1-azabicyclo-  butyryl]amino]-8-oxo-5-thia-1-aza-         [4.2.0]oct-2-ene-2-carboxylic      bicyclo[4.2.0]oct-2-ene-2-carboxylic       acid                               acid                                       3-[(acetyloxy)methyl]-7-[[2-[4-                                                                     isothiourea  3-[(acetyloxy)methyl]-7-[[2-[4-(iso-       (chloromethyl)phenyl]acetyl]amino]-                                                                              thioureamethyl)phenyl]acetyl]amino]-       8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-                                                                           8-oxo-5-thia-1-azabicyclo[4.2.0]oct-       ene-2-carboxylic acid 2-amino-3-methyl-                                                                          2-ene-2-carboxylic acid 2-amino-3-         butyryloxymethyl ester             methylbutyryloxymethyl ester               3-[(acetyloxy)methyl]-7-[[2-[4-(chlo-                                                               1-ethylisothiourea                                                                         3-[(acetyloxy)methyl]-7-[[2-[4-(1-         romethyl)phenyl]acetyl]amino]-8-oxo-                                                                             ethylisothioureamethyl)phenyl]acetyl]-     5-thia-1-azabicyclo[4.2.0]oct-2-ene-                                                                             amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]                                       -                                          2-carboxylic acid pivalyloxymethyl oct-2-ene-2-carboxylic acid                                                   pivalyloxy-                                ester                              methyl ester                               6-[[3-[4-(chloromethyl)phenyl]-2-meth-                                                              1,3-diethylisothiourea                                                                     6-[[3-[4-(1,3-diethylisothioureamethyl)                                       -                                          ylpropionyl]amino]-3,3-dimethyl-7-oxo-                                                                           phenyl]-2-methylpropionyl]amino]-3,3-      4-thia-1-azabicyclo[3.2.0]heptane-2-                                                                             dimethyl-7-oxo-4-thia-1-azabicyclo-        carboxylic acid                    [3.2.0]heptane-2-carboxylic acid           6-[[4-[4-(chloromethyl)phenyl]-2-meth-                                                              1,1-dimethyl-3-ethyl-                                                                      6-[[4-[4-(1,1-dimethyl-3-ethylisothio-     ylbutyryl]amino]-3,3-dimethyl-7-oxo-                                                                isothiourea  ureamethyl)phenyl]-2-methylbutyryl]-       4-thia-1-azabicyclo[3.2.0]heptane-2-                                                                             amino]-3,3-dimethyl-7-oxo-4-thia-1-        carboxylic acid                    azabicyclo[3.2.0]heptane-2-carboxylic                                         acid                                       6-[[2-[4-(chloromethyl)phenoxy]acetyl)-                                                             isothiourea  6-[[2-[4-(isothioureamethyl)phenoxy]-      amino]-3,3-dimethyl-7-oxo-4-thia-1-                                                                              acetyl]amino]-3,3-dimethyl-7-oxo-4-        azabicyclo[3.2.0]heptane-2-carboxylic                                                                            thia-1-azabicyclo[3.2.0]heptane-2-         acid                               carboxylic acid                            6-[[2-[4-(chloromethyl)phenoxy]-2-                                                                  isothiourea  6-[[2-[4-(isothioureamethyl)phenoxy]-2-    methylacetyl]amino]-3,3-dimethyl-7-                                                                              methylacetyl]amino]3,3-dimethyl-7-oxo-     oxo-4-thia-1-azabicyclo[3.2.0]hep- 4-thia-1-azabicyclo[3.2.0]heptane-2-       tane-2-carboxylic acid             carboxylic acid                            3-(2-methyl-1,3,4-thiadiazol-5-yl                                                                   isothiourea  3-(2-methyl-1,3,4-thiadiazol-5-ylthio]-    thio]-7-[[2-[4-(chloromethyl)phenyl]-                                                                            7-[[2-[4-isothioureamethyl)phenyl]ace-     acetyl]amino]-8-oxo-5-thia-1-azabicy-                                                                            tyl]amino]-8-oxo-5-thia-1-azabicyclo-      clo[4.2.0]amino]-8-oxo-5-thia-1-azabi-                                                                           [4.2.0]oct-2-ene-2-carboxylic acid         cyclo[4.2.0]oct-2-ene-2-carboxylic acid                                       6-[[2-[4-(chloromethyl)anilino]-                                                                    1-methyl-3-ethyl-                                                                          6-[[2-[4-(1-methyl-3-ethyl-isothio-        acetyl]amino]-3,3-dimethyl-7-oxo-                                                                   isothiourea  ureamethyl)anilino]acetyl]amino]-3,3-      4-thia-1-azabicyclo[3.2.0]heptane- dimethyl-7-oxo-4-thia-1-azabicyclo-        2-carboxylic acid                  [3.2.0]heptane-2-carboxylic acid           6-[[3-[4-(chloromethyl)anilino]-                                                                    isothiourea  6-[[3-[4-(isothioureamethyl)anilino]-      2-methylpropionyl]amino]-3,3-di-   2-methylpropionyl]amino]-3,3-dimethyl-     methyl-7-oxo-4-thia-1-azabicyclo-  7-oxo-4-thia-1-azabicyclo[3.2.0]hep-       [3.2.0]heptane-2-carboxylic acid   tane-2-carboxylic acid                     6-[[2-[4-(chloromethyl)phenylthio]-                                                                 1,3-di-n-butyl-                                                                            6-[[2-[4-(1,3-di-n-butylisothiourea-       acetyl]amino]-3,3-dimethyl-7-oxo-                                                                   isothiourea  methyl)phenylthio]acetyl]amino]-3,3-       4-thia-1-azabicyclo[3.2.0]heptane- dimethyl-7-oxo-4-thia-1-azabicyclo-        2-carboxylic acid                  [3.2.0]heptane-2-carboxylic acid           6-[[2-[2-(chloro)-4-(chloromethyl)-                                                                 isothiourea  6-[[2-[2-(chloro-4-(isothioureamethyl)-    phenyl]acetyl]amino]-3,3-dimethyl- phenyl]acetyl]amino]-3,3-dimethyl-7-       7-oxo-4-thia-1-azabicyclo[3.2.0]-  oxo-4-thia-1-azabicyclo[3.2.0]heptane-     heptane-2-carboxylic acid          2-carboxylic acid                          6-[[4-[4-(chloromethyl)phenyl-                                                                      1,1-diethyl-3-                                                                             6-[[4-[4-(1,1-diethyl-3-methyliso-         thio]butyryl]amino]-3,3-dimethyl-                                                                   methylisothiourea                                                                          thioureamethyl)phenylthio]butyryl]-        7-oxo-4-thia-1-azabicyclo[3.2.0]-  amino]-3,3-dimethyl-7-oxo-4-thia-1-        heptane-2-carboxylic acid          azabicyclo[3.2.0]heptane-2-carboxylic                                         acid                                       3-[(acetyloxy)methyl]-7-[[3-[4-                                                                     1,3-diethylisothiourea                                                                     3-[(acetyloxy)methyl]-7-[[3-[4-(1,3-       (chloromethyl)phenyl]-2-hydroxy-   diethylisothioureamethyl)phenyl]-2-        propionyl]amino]-8-oxo-5-thia-     hydroxypropionyl]amino]-8-oxo-5-thia-      1-azabicyclo[4.2.0]oct-2-ene-      1-azabicyclo[4.2.0]  oct-2-ene-2-          2-carboxylic acid                  carboxylic acid                            3-[(acetyloxy)methyl]-7-[[4-[4-                                                                     1-ethylisothiourea                                                                         3-[(acetyloxy)methyl]-7-[[4-[4-(1-         (chloromethyl)phenyl]-2-hydroxy-   ethylisothioureamethyl)phenyl]-2-          butyryl]amino]-8-oxo-5-thia-1-     hydroxybutyryl]amino]-8-oxo-5-thia-1-      azabicyclo[4.2.0]oct-2-ene-2-      azabicyclo[4.2.0]oct-2-ene-2-carbox-       carboxylic acid                    ylic acid                                  3-[(acetyloxy)methyl]-7-[[2-[5-                                                                     3-n-propylisothiourea                                                                      3-[(acetyloxy)methyl]-7-[[2-[5-(3-n-       (chloromethyl)-2-thienyl]-2-       propylisothioureamethyl)-2-thienyl]-       hydroxyacetyl]amino]-8-oxo-5-      2-hydroxyacetyl]amino]-8-oxo-5-thia-       thia-1-azabicyclo[4.2.0]oct-       1-azabicyclo[4.2.0]oct-2-ene-2-            2-ene-2-carboxylic acid            carboxylic acid                            6-[[3-[4-(chloromethyl)phenyl]-                                                                     1,3-dimethyliso-                                                                           6-[[3-[4-(1,3-dimethylisothiourea-         2-hydroxypropionyl]amino]-3,3-                                                                      thiourea     methyl)phenyl]-2-hydroxypropionyl]-        dimethyl-7-oxo-4-thia-1-azabicy-   amino]-3,3-dimethyl-7-oxo-4-thia-1-        clo[3.2.0]heptane-2-carboxylic     azabicyclo[3.2.0]heptane-2-carboxylic      acid                               acid                                       3-(1-methyltetrazol-5-ylthio)-7-                                                                    isothiourea  3-(1-methyltetrazol-5-ylthio)-7-[[2-[4-    [[2-[4-(chloromethyl)phenyl]acetyl]-                                                                             isothioureamethyl)phenyl]acetyl]amino]-    amino]-8-oxo-5-thia-1-azabicyclo-  8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-     [4.2.0]oct-2-ene-2-carboxylic acid ene-2-carboxylic acid                      6-[[2-[5-(chloromethyl)-2-thienyl]-                                                                 1,3-di-n-butyl-                                                                            6-[[2-[5-(1,3-di-n-butylisothiourea-       2-hydroxyacetyl]amino]-3,3-dimethyl-                                                                isothiourea  methyl)-2-thienyl]-2-hydroxyacetyl]-       7-oxo-4-thia-1-azabicyclo[3.2.0]-  amino]-3,3-dimethyl-7-oxo-4-thia-1-        heptane-2-carboxylic acid          azabicyclo[3.2.0]heptane-2-carboxylic                                         acid                                       3-[(acetyloxy)methyl]-7-[[2-[4-                                                                     1-methyl-3-ethyl-                                                                          3-[(acetyloxy)methyl]  -7-[[2-[4-(1-       (chloromethyl)phenyl]-2-sulfo-                                                                      isothiourea  methyl-3-ethylisothioureamethyl)-          acetyl]amino]-8-oxo-5-thia-1-      phenyl]-2-sulfoacetyl]amino]-8-oxo-        azabicyclo[4.2.0]oct-2-ene-2-      5-thia-1-azabicyclo[4.2.0]oct-2-ene-       carboxylic acid                    2-carboxylic acid                          3-[(acetyloxy)methyl]-7-[[4-[4-                                                                     1-ethyl-3-isopro-                                                                          3-[(acetyloxy)methyl]-7-[[4-[4-(1-         (chloromethyl)phenyl]-2-sulfo-                                                                      pylisothiourea                                                                             ethyl-3-isopropylisothioureamethyl)-       butyryl]amino]-8-oxo-5-thia-1-     phenyl]-2-sulfobutyryl]amino]-8-oxo-       azabicyclo[4.2.0]oct-2-ene-2-car-  5-thia-1-azabicyclo[4.2.0]oct-2-ene-       boxylic acid                       2-carboxylic acid                          3-[(acetyloxy)methyl]-7-[[3-[4-                                                                     1,1,3-triethyl-                                                                            3-[(acetyloxy)methyl]-7-[[3-[4-(1,1,3-     (chloromethyl)phenyl]-2-carboxypro-                                                                 isothiourea  triethylisothioureamethyl)phenyl]-2-       pionyl]amino]-8-oxo-5-thia-1-aza-  carboxypropionyl]amino]-8-oxo-5-thia-      bicyclo[4.2.0]oct-2-ene-2-car-     1-azabicyclo[4.2.0]oct-2-ene-2-car-        boxylic acid                       boxylic acid                               3-[(acetyloxy)methyl]-7-[[4-[4-                                                                     1,1-di-n-propyl-3-                                                                         3-[(acetyloxy)methyl]-7-[[4-[4-(1,1-       (chloromethyl)phenoxy]-2-carboxy-                                                                   methylisothiourea                                                                          di-n-propyl-3-methylisothioureamethyl)-    butyryl]amino]-8-oxo-5-thia-1-     phenoxy]-2-carboxybutyryl]amino]-8-oxo-    azabicyclo[4.2.0]oct-2-ene-2-      5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-     carboxylic acid                    carboxylic acid                            3-[(acetyloxy)methyl]-7-[[4-[4-                                                                     1,3-di-sec-butyl-                                                                          3-[(acetyloxy)methyl]-7-[[4-[4-(1,3-       (chloromethyl)phenylthio]-2-carboxy-                                                                isothiourea  di-sec-butylisothioureamethyl)phenyl-      butyryl]amino]-8-oxo-5-thia-1-aza- thio]-2-carboxybutyryl]amino]-8-oxo-       bicyclo[4.2.0]oct-2-ene-2-carboxylic                                                                             5-thia-1-azabicyclo[4.2.0]oct-2-ene-       acid                               2-carboxylic acid                          3-[(acetyloxy)methyl]-7-[[3-[4-                                                                     1,3-di-n-propyliso-                                                                        3-[(acetyloxy)methyl]-7-[[3-[4-(1,3-       (chloromethyl)anilino]-2-carboxypro-                                                                thiourea     di-n-propylisothioureamethyl)anilino]-     pionyl]amino]-8-oxo-5-thia-1-aza-  2-carboxypropionyl]amino]-8-oxo-5-         bicyclo[4.2.0]oct-2-ene-2-carboxylic                                                                             thia-1-azabicyclo[4.2.0]oct-2-ene-2-       acid                               carboxylic acid                            3-[(acetyloxy)methyl]-7-[[3-[5-                                                                     1-n-butyl-3-methyl-                                                                        3-[(acetyloxy)methyl]-7-[[3-[5-(1-n-       (chloromethyl)-2-thienyl]-2-                                                                        isothiourea  butyl-3-methylisothioureamethyl)-2-        carboxypropionyl]amino]-8-oxo-     thienyl]-2-carboxypropionyl]amino]-8-      5-thia-1-azabicyclo[4.2.0]oct-     oxo-5-thia-1-azabicyclo[4.2.0]oct-2-       2-ene-2-carboxylic acid            ene-2-carboxylic acid                      6-[[2-[4-(chloromethyl]phenyl]-2-                                                                   1-ethyl-3-methyl-                                                                          6-[[2-[4-(1-ethyl-3-methylisothiourea-     sulfoacetyl]amino]-3,3-dimethyl-                                                                    isothiourea  methyl)phenyl]2-sulfoacetyl]amino]-3,3-    7-oxo-4-thia-1-azabicyclo[3.2.0]-  dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.                                       0]-                                        heptane-2-carboxylic acid          heptane-2-carboxylic acid                  6-[[4-[4-(chloromethyl)phenyl]-                                                                     isothiourea  6-[[4-[4-(isothioureamethyl)phenyl]-2-     2-sulfobutyryl]amino]-3,3-dimethyl-                                                                              sulfobutyryl]amino]-3,3-dimethyl-7-oxo-    7-oxo-4-thia-1-azabicyclo[3.2.0]-  4-thia-1-azabicyclo[3.2.0]heptane-2-       heptane-2-carboxylic acid          carboxylic acid                            6-[[3-[4-(chloromethyl)phenyl]-2-                                                                   1-ethyl-3-n-propyl-                                                                        6-[[3-[4-(1-ethyl-3-n-propylisothio-       carboxypropionyl]amino]-3,3-dimethyl-                                                               isothiourea  ureamethyl)phenyl]-2-carboxypropionyl]-    7-oxo-4-thia-1-azabicyclo[3.2.0]-  amino]-3,3-dimethyl-7-oxo-4-thia-1-        heptane-2-carboxylic acid          azabicyclo[3.2.0]heptane-2-carboxylic                                         acid                                       6-[[4-[4-(chloromethyl)phenoxy]-2-                                                                  1-ethyl-3-n-butyl-                                                                         6-[[4-[4-(1-ethyl-3-n-butylisothio-        carboxybutyryl]amino]-3,3-dimethyl-                                                                 isothiourea  ureamethyl)phenoxy]                                                           -2-carboxybutyryl]-                        7-oxo-4-thia-1-azabicyclo[3.2.0]-  amino]-3,3-dimethyl-7-oxo-4-thia-1-        heptane-2-carboxylic acid          azabicyclo[3.2.0]heptane-2-carboxylic                                         acid                                       6-[[4-[4-(chloromethyl)phenylthio]-                                                                 1,1-di-n-propyl-3-                                                                         6-[[4-[4-(1,1-di-n-propyl-3-ethyliso-      2-carboxybutyryl]amino]-3,3-di-                                                                     ethylisothiourea                                                                           thioureamethyl)phenylthio]-2-carboxy-      methyl-7-oxo-4-thia-1-azabicyclo-  butyryl]amino]-3,3-dimethyl-7-oxo-4-       [3.2.0]heptane-2-carboxylic acid   thia-1-azabicyclo[3.2.0]heptane-2-                                            carboxylic acid                            3-(2-methyl-1,3,4-thiadiazol-5-yl-                                                                  isothiourea  3-(2-methyl-1,3,4-thiadiazol-5-ylthio)-    thio)-7-[[2-[4-(chloromethyl)-     7-[[2-[4-(isothioureamethyl)phenyl]-2-     phenyl]-2-hydroxyacetyl]amino]-8-  hydroxyacetyl]amino]-8-oxo-5-thia-1-       oxo-5-thia-1-azabicyclo[4.2.0]oct- azabicyclo[4.2.0]oct-2-ene-2-carboxylic    2-ene-2-carboxylic acid            acid                                       3-(1-methyltetrazol-5-ylthio)-7-                                                                    isothiourea  3-(1-methyltetrazol-5-ylthio)-7-[[2-[4-    [[2-[4-(chloromethyl)phenyl]-2-    (isothioureamethyl)phenyl]-2-hydroxy-      hydroxyacetyl]amino]-8-oxo-5-thia- acetyl]amino]-8-oxo-5-thia-1-azabicyclo                                       -                                          1-azabicyclo[4.2.0]oct-2-ene-2-    [4.2.0]oct-2-ene-2-carboxylic acid         carboxylic acid                                                               3-(2-methyl-1,3,4-thiadiazol-5-yl-                                                                  isothiourea  3-(2-methyl-1,3,4-thiadiazol-5-ylthio)-    thio)-7-[[2-[4-(chloromethyl)phenyl]-                                                                            7-[[2-[4-(isothioureamethyl)phenyl]-2-     2-carboxyacetyl]amino]-8-oxo-5-thia-                                                                             carboxyacetyl]amino]-8-oxo-5-thia-1-       1-azabicyclo[4.2.0]oct-2-ene-2-car-                                                                              azabicyclo[4.2.0]oct-2-ene-2-carbox-       boxylic acid                       ylic acid                                  3-[(acetyloxy)methyl]-7-[[2-[4-(chlo-                                                               isothiourea  3-[(acetyloxy)methyl]-7-[[2-[4-(iso-       romethyl)phenyl]-2-carboxyacetyl]- thioureamethyl)phenyl]-2-carboxyace-       amino]-8-oxo-5-thia-1-azabicyclo-  tyl]amino]-8-oxo-5-thia-1-azabicyclo-      [4.2.0]oct-2-ene-2-carboxylic acid [4.2.0]oct-2-ene-2-carboxylic acid         3-(1-methyltetrazol-5-ylthio)-7-[[2-                                                                isothiourea  3-(1-methyltetrazol-5-ylthio)-7-[[2-       [4-(chloromethyl)phenyl]-2-carboxy-                                                                              [4-(isothioureamethyl)phenyl]-2-car-       acetyl]amino]-8-oxo-5-thia-1-azabicy-                                                                            boxyacetyl]amino]-8-oxo-5-thia-1-aza-      clo[4.2.0]oct-2-ene-2-carboxylic   bicyclo[4.2.0]oct-2-ene-2-carboxylic       acid pivalyloxybenzyl ester        acid pivalyloxybenzyl ester                3-[(acetyloxy)methyl]-7-[[2-[4-(chlo-                                                               isothiourea  3-[(acetyloxy)methyl]-7-[[2-[4-(iso-       romethyl)phenyl]-2-hydroxyacetyl]- thioureamethyl)phenyl]-2-hydroxyace-       amino]-8-oxo-5-thia-1-azabicyclo-  tyl]amino]-8-oxo-5-thia-1-azabicyclo-      [4.2.0]oct-2-ene-2-carboxylic acid [4.2.0]oct-2-ene-2-carboxylic acid         7-[[2-[4-(chloromethyl)phenyl]acetyl]-                                                              isothiourea  7-[[2-[4-(isothioureamethyl)phenyl]-       amino]-3-methyl-8-oxo-5-thia-1-aza-                                                                              acetyl]amino]-3-methyl-8-oxo-5-thia-       bicyclo[4.2.0]oct-2-ene-2-carbox-  1-azabicyclo[4.2.0]oct-2-ene-2-car-        ylic acid                          boxylic acid                               __________________________________________________________________________

EXAMPLE 283-[(Acetyloxy)methyl]-7-[[2-[4-(isothioureamethyl)phenyl]-2-aminoacetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

A. A mixture of 7.5 g of3-[(acetyloxy)methyl]-7-[[2-[4-(chloromethyl)phenyl]-2-aminoacetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid wherein the 2-amino group is protected with hydrochloride salt and1.03 g of isothiourea in 50 ml of ethanol is heated for several hours atreflux after which the solvent is removed in vacuo at room temperatureyielding an oil. The oil is triturated with 2:1 benzene-acetone to givethe corresponding isothioureamethyl derivative.

B. At 0° C 10 ml of trifluoroacetic acid is added to 5g of3-[(acetyloxy)methyl]-7-[[2-[4-(isothioureamethyl)phenyl]-2-aminoacetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid wherein the 2-amino group is protected with tert-butoxycarbonylobtained in (A) above. The mixture is stirred for several minutes undera nitrogen atmosphere resulting in a clear solution which is stirred anadditional 15 minutes at room temperature. The excess trifluoroaceticacid is removed in vacuo, and the remaining residue is triturated withdiethylether then dissolved in 175 ml of water. The solution is filteredand the pH of the filtrate adjusted to 5.5 by adding Amberlite IR4Bresin that had been washed several times with water. The resin isfiltered off and the water concentrated in vacuo. A precipitate formsfrom the concentrate which is removed and washed with ethanol to give3-[(acetyloxy)methyl]-7-[[2-[4-(isothioureamethyl)phenyl]-2-aminoacetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid.

In a similar manner when the halomethylated derivative and theisothiourea derivative listed in the following Table X are reacted as inExample 28(A) and the resulting product subsequently treated as inExample 28(B) the respective products listed in Table X are obtained.

                                      TABLE X                                     __________________________________________________________________________    Halomethylated Derivative                                                                          Isothiourea Derivative Product                           __________________________________________________________________________    6-[[2-[4-(chloromethyl)phenyl]-                                                                    n-propylisothiourea                                                                         6-[[2-[4-(n-propylisothioureamethyl)-      2-aminoacetyl]amino]-3,3-dimethyl- phenyl]-2-aminoacetyl]amino]-3,3-di-       7-oxo-4-thia-1-azabicyclo[3.2.0]-  methyl-7-oxo-4-thia-1-azabicyclo-          heptane-2-carboxylic acid          [3.2.0]heptane-2-carboxylic acid           3-[(acetyloxy)methyl]-7-[[3-[4-                                                                    1-ethyl-3-methyliso-                                                                        3-[(acetyloxy)methyl]-7-[[3-[4-(1-         (chloromethyl)phenyl]-2-amino-                                                                     thiourea      ethyl-3-methylisothioureamethyl)-          propionyl]amino]-8-oxo-5-thia-     phenyl]-2-aminopropionyl]amino]-8-         1-azabicyclo[4.2.0]oct-2-ene-2-    oxo-5-thia-1-azabicyclo[4.2.0]oct-         carboxylic acid                    2-ene-2-carboxylic acid                    3-[(acetyloxy)methyl]-7-[[4-[4-                                                                    isothiourea   3-[(acetyloxy)methyl]-7-[[4-[4-(iso-       (chloromethyl)phenoxy]-2-amino-    thioureamethyl)phenoxy]-2-aminobutyryl]                                       -                                          butyryl]amino]-8-oxo-5-thia-1-     amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]                                       -                                          azabicyclo[4.2.0]oct-2-ene-2-      oct-2-ene-2-carboxylic acid                carboxylic acid                                                               3-[(acetyloxy)methyl]-7-[[4-[4-                                                                    isothiourea   3-[(acetyloxy)methyl]-7-[[4-[4-(iso-       (chloromethyl)anilino]-2-amino-    thioureamethyl)anilino]-2-amino-           butyryl]amino]-8-oxo-5-thia-1-     butyryl]amino]-8-oxo-5-thia-1-azabicy-     azabicyclo[4.2.0]oct-2-ene-2-      clo[4.2.0]oct-2-ene-2-carboxylic acid      carboxylic acid                                                               3-[(acetyloxy)methyl]-7-[[3-[4-                                                                    isothiourea   3-[(acetyloxy)methyl]-7-[[3-[4-(iso-       (chloromethyl)phenylthio]-2-       thioureamethyl)phenylthio]-2-amino-        aminopropionyl]amino]-8-oxo-5-     propionyl]amino]-8-oxo-5-thia-1-aza-       thia-1-azabicyclo[4.2.0]oct-2-     bicyclo[4.2.0]oct-2-ene-2-carboxylic       ene-2-carboxylic acid              acid                                       3-[(acetyloxy)methyl]-7-[[2-[  5-                                                                  1,3-di-n-propyliso-                                                                         3-[(acetyloxy)methyl)-7-[[2-[5-(1,3-       (chloromethyl)-2-thienyl]-2-                                                                       thiourea      di-n-propylisothioureamethyl)-2-           aminoacetyl]amino]-8-oxo-5-thia-   thienyl]-2-aminoacetyl]amino]-8-oxo-       1-azabicyclo[4.2.0]oct-2-ene-2-    5-thia-1-azabicyclo[4.2.0]oct-2-ene-       carboxylic acid                    2-carboxylic acid                          3-[(acetyloxy)methyl]-7-[[4-[5-                                                                    1-ethylisothiourea                                                                          3-[(acetyloxy)methyl]-7-[[4-[5-(1-         (chloromethyl)-2-thienyl]-2-       ethylisothioureamethyl)-2-thienyl]-2-      aminobutyryl]amino]-8-oxo-5-       aminobutyryl]amino]-8-oxo-5-thia-1-        thia-1-azabicyclo[4.2.0]oct-2-     azabicyclo[4.2.0]oct-2-ene-2-carbox-       ene-2-carboxylic acid              ylic acid                                  6-[[3-[4-(chloromethyl)phenyl]-2-                                                                  isothiourea   6-[[3-[4-(isothioureamethyl)phenyl]-2-     aminopropionyl]amino]-3,3-di-      aminopropionyl]amino]-3,3-dimethyl-7-      methyl-7-oxo-4-thia-1-azabicyclo-  oxo-4-thia-1-azabicyclo[3.2.0]heptane-     [3.2.0]heptane-2-carboxylic acid   2-carboxylic acid                          6-[[4-[4-(chloromethyl)phenoxy]-2-                                                                 isothiourea   6-[[4-[4-(isothioureamethyl)phenoxy]-      aminobutyryl]amino]-3,3-dimethyl-  2-aminobutyryl]amino]-3,3-dimethyl-7-      7-oxo-4-thia-1-azabicyclo[3.2.0]-  oxo-4-thia-1-azabicyclo[3.2.0]heptane-     heptane-2-carboxylic acid          2-carboxylic acid                          6-[[4-[4-(chloromethyl)anilino]-2-                                                                 1,3-diethylisothiourea                                                                      6-[[4-[4-(1,3-diethylisothiourea-          aminobutyryl]amino-3,3-dimethyl-7- methyl)anilino]-2-aminobutyryl]-           oxo-4-thia-1-azabicyclo[3.2.0]-    amino-3,3-dimethyl-7-oxo-4-thia-1-         heptane-2-carboxylic acid          azabicyclo[3.2.0]heptane-2-carboxylic                                         acid                                       6-[[3-[4-(chloromethyl)phenylthio]-                                                                1,1-dimethyl-3-ethyliso-                                                                    6-[[3-[4-(1,1-dimethyl-3-ethylisothio-     2-aminopropionyl]amino]-3,3-di-                                                                    thiourea      ureamethyl)phenylthio]-2-aminopropio-      methyl-7-oxo-4-thia-1-azabicyclo-  nyl]amino]  -3,3-dimethyl-7-oxo-4-thia-    [3.2.0]heptane-2-carboxylic acid   1-azabicyclo[3.2.0]heptane-2-carbox-                                          ylic acid                                  6-[[2-[5-(chloromethyl)-2-thienyl]-                                                                isothiourea   6-[[2-[5-(isothioureamethyl)-2-thi-        2-aminoacetyl]amino]-3,3,-dimethyl-                                                                              enyl]-2-aminoacetyl]amino]-3,3-di-         7-oxo-4-thia-1-azabicyclo[3.2.0]-  methyl-7-oxo-4-thia-1-azabicyclo[3.2.0]                                       -                                          heptane-2-carboxylic acid          heptane-2-carboxylic acid                  3-(2-methyl-1,3,4-thiadiazol-5-yl-                                                                 isothiourea   3-(2-methyl-1,3,4-thiadiazol-5-ylthio)-    thio)-7-[[2-[4-(chloromethyl)phenyl]-                                                                            7-[[2-[4-(isothioureamethyl)phenyl]-2-     2-aminoacetyl]amino]-8-oxo-5-thia-1-                                                                             aminoacetyl]amino]-8-oxo-5-thia-1-aza-     azabicyclo[4.2.0]oct-2-ene-2-carbox-                                                                             bicyclo[4.2.0]oct-2-ene-2-carboxylic       ylic acid                          acid                                       3-[(acetyloxy)methyl]-7-[[2-[4-(chlo-                                                              isothiourea   3-[(acetyloxy)methyl]-7-[[2-[4-(iso-       romethyl)phenyl]-2-aminoacetyl]amino]-                                                                           thioureamethyl)phenyl]-2-aminoacetyl]-     8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-                                                                           amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]                                       -                                          ene-2-carboxylic acid pivalyloxymethyl                                                                           oct-2-ene-2-carboxylic acid                                                   pivalyloxy-                                ester                              methyl ester                               3-(1-methyltetrazol-5-ylthio)-7-                                                                   isothiourea   3-(1-methyltetrazol-5-ylthio)-7-[[2-       [[2-[4-(chloromethyl)phenyl]-2-    [4-(isothioureamethyl)phenyl]-2-amino-                                        7                                          aminoacetyl]amino]-8-oxo-5-thia-   acetyl]amino]-8-oxo-5-thia-1-azabicy-      1-azabicyclo[4.2.0]oct-2-ene-2-    clo[4.2.0]oct-2-ene-2-carboxylic acid      carboxylic acid                                                               __________________________________________________________________________

EXAMPLE 293-[(Acetyloxy)methyl]-7-[[2-[4-(isothioureamethyl)phenyl]-acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid -N-ethoxycarbonyl-N-methylaminomethyl ester

A mixture of 1.2 g of the sodium salt of3-[(acetyloxy)methyl]-7-[[2-[4-(isothioureamethyl]phenyl]acetyl]-amino]-8-oxo-5-thia-1-azabicyclo[4.2.0] oct-2-ene-2-carboxylic acid and 0.5 g ofN-chloromethyl-N-methylurethane in 40 ml of dimethylformamide is stirredat room temperature for 2 hours. The mixture is poured into ice-waterand decanted. The oily residue is taken up in 75 ml of ethyl acetate andwashed with 5 ml of dilute aqueous sodium bicarbonate and 15 ml of waterthen dried over magnesium sulfate, filtered and evaporated to give3-[(acetyloxy)methyl]-7-[[2-[4-(isothioureamethyl)phenyl]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid N-ethoxycarbonyl-N-methylaminomethyl ester.

EXAMPLE 303-[(Acetyloxy)methyl]-7-[[2-[4-(isothioureamethyl)-phenyl]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ene-2-carboxylicacid-p-pivalyoxybenzyl ester

To a solution of 1.8 g of3-[(acetyloxy)methyl]-7-[[2-[4-(isothioureamethyl)phenyl]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid hydrochloride in 25 ml of dimethyl formamide is added 0.78 g ofp-pivalyoxybenzyl alcohol followed by cooling to 0° C after which 3.7mole of dicyclohexylcarbodiimide in 7.5 ml of dimethyl formamide isadded dripwise with stirring. The reaction mixture is stirred for 1 hourat 0° C and for an additional 4 hours at room temperature. The formeddicyclohexylurea is removed by filtration. The filtrate is diluted withchloroform and washed with water. The organic layer is then dried overmagnesium sulfate filtered and evaporated in vacuo to give an oil whichis triturated with ether to give3-[(acetyloxy)methyl]-7-[[2-[4-(isothioureamethyl)phenyl]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid p-pivalyloxybenzyl ester.

EXAMPLE 31

A. When in the procedure of Example 14 an appropriate amount of3-(acetyloxy]methyl]-7-amino-7-methoxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid, prepared by acid hydrolysis of the corresponding benzhydryl esterdescribed in U.S. Pat. No. 3,778,432, or the corresponding3-(2-methyl-1,3,4-thiadiazol-5-ylthio derivative is substituted for3-[(acetyloxy)-methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid,3-[(acetyloxy)methyl]-7-[[2-[4-(chloromethyl)phenyl]acetyl]amino]-7-methoxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid and the corresponding 3-(2-methyl-1,3,4-thiadiazol-5-ylthioderivative are obtained respectively.

B. When in the procedure of Example 27 appropriate amounts of each ofthe above obtained 7-methoxy derivatives are substituted for3-[(acetyloxy)methyl]-7-[[2-[4-(chloromethyl)phenyl]acetyl]amino]-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylicacid,3-[(acetyloxy)methyl]-7-[[2-[4-(isothioureamethyl)phenyl]acetyl]amino]-7-methoxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid and3-(2-methyl-1,3,4-thiadiazol-5-ylthio)-7-[[2-[4-(isothioureamethyl)phenyl]acetyl]amino]-7-methoxy-8-oxo-5-thia-1-azabicyclo]4.2.0]oct-2-ene-2-carboxylicacid are obtained.

EXAMPLE 323-](Acetyloxy)methyl]-7-[[2-[4-(isothioureamethyl)phenyl]-2-(5-indanyloxycarbonyl)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0oct-2-ene-2-carboxylic acid

To 25.3 m mole of the cephalosporin in 35 ml dioxane is added 6Nhydrochloric acid to give a pH of 2.5. Then 24.1 m molesN,N'-dicyclohexylcarbodiimide in 35 ml dioxane is added and the mixtureis stirred at room temperature for 15 to 20 minutes followed by theaddition of 24.1 m moles of 5-indanol. The mixture is stirred for 4hours. The formed N,N'-dicyclohexylurea is removed by filtration and thefiltrate is extracted three times with methyl isobutyl ketone. Theorganic extract is washed with water, dried over magnesium sulfate andconcentrated to dryness in vacuo to yield3-[(acetyloxy)methyl]-7-[[2-[4-(isothioureamethyl]phenyl]-2-(5-indanyloxycarbonyl)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.

EXAMPLE 33 o-Isothioureamethylphenylacetic acid hydrochloride

A solution of 0.25 g (1.33 mM) of p-chlorophenylacetic acid and 0.25 g(3.33 mM) of isothiourea is refluxed in 65 ml of ethanol for 31/2 hoursafter which the solvent is removed in vacuo at room temperature. Theresulting oil is triturated with 110 ml of acetone/benzene (1:2) to givep-isothioureamethylphenylacetic acid hydrochloride as a white solid,M.P. 173°-175° C.

In a similar manner when appropriate amounts of the acid derivatives andisothiourea derivatives listed below in Table XI are substitutedrespectively for p-chlorophenylacetic acid and isothiourea in the aboveprocedure the respective products listed in Table XI are obtained.

                                      TABLE XI                                    __________________________________________________________________________           Acid         Isothiourea Derivative                                                                           Product                                __________________________________________________________________________    p-chloromethyl-2-methylhydro-                                                                     isothiourea  p-isothioureamethyl-2-methylhydro-           cinnamic acid                    cinnamic acid hydrochloride                  3-(p-chloromethylphenyl)lactic acid                                                               isothiourea  3-(p-isothioureamethylphenyl)lactic                                           acid hydrochloride                           4-(p-chloromethylphenyl)butyric acid                                                              n-propylisothiourea                                                                        4-(p-n-propylisothioureamethylphenyl)-                                        butyric acid hydrochloride                   p-chloromethylphenoxyacetic acid                                                                  isothiourea  p-isothioureamethylphenoxyacetic acid                                         hydrochloride                                2-(p-chloromethylphenoxy)propionic                                                                1,1-diethyl-3-methyl-                                                                      2-[p-(1,1-diethyl-3-methylisothiourea-       acid                isothiourea  methyl)phenoxy]propionic acid hydro-                                          chloride                                     4-(p-chloromethylphenoxy)butyric acid                                                             isothiourea  4-(p-isothioureamethylphenoxy)butyric                                         acid hydrochloride                           2-(p-chloromethylanilino)propionic                                                                isothiourea  2-(p-isothioureamethylanilino)propion-       acid                             ic acid hydrochloride                        4-(p-chloromethylanilino)butyric acid                                                             n-propylisothiourea                                                                        4-(p-n-propylisothioureamethylanilino)-                                       butyric acid hydrochloride                   p-chloromethylphenylthioacetic acid                                                               1-ethyl-3-methyl-                                                                          p-(1-ethyl-3-methylisothioureamethyl)-                           isothiourea  phenylthioacetic acid hydrochloride          2-amino-4-(p-chloromethylphenyl)-                                                                 isothiourea  2-amino-4-(p-isothioureamethylphenyl)-       butyric acid                     butyric acid hydrochloride                   2-amino-4-(p-chloromethylphenoxy)-                                                                isothiourea  2-amino-4-(p-isothioureamethylphenoxy)-      butyric acid                     butyric acid hydrochloride                   2-amino-4-(p-chloromethylanilino)-                                                                isothiourea  2-amino-4-(p-isothioureamethylanilino)-      butyric acid                     butyric acid hydrochloride                   2-sulfo-p-chloromethylphenylacetic                                                                1,1-diethylisothiourea                                                                     2-sulfo-p-(1,1-diethylisothioureameth-       acid                             yl)phenylacetic acid hydrochloride           p-chloromethylphenylmalonic acid                                                                  isothiourea  p-isothioureamethylphenylmalonic acid                                         hydrochloride                                2-(p-chloromethylphenoxy)ethyl-                                                                   n-propylisothiourea                                                                        2-(p-n-propylisothioureamethylphenoxy)-      malonic acid                     ethylmalonic acid hydrochloride              p-chloromethylanilinomethylmalonic                                                                isothiourea  p-isothioureamethylanilinomethyl-            acid                             malonic acid hydrochloride                   __________________________________________________________________________

EXAMPLE 343-[(Acetyloxy)methyl]-7-[[2-[4-(isothioureamethyl)phenyl]-acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

A mixture of 1.2 grams of3-[(acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid and 1.2 grams of p-isothioureamethylphenylacetic acid chloride HClin 55 ml of ethyl acetate is refluxed for 11/2 hours after which thesolvent is removed yielding3-[(acetyloxy)methyl]-7-[[2-[4-(isothioureamethyl)phenyl]-acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid which can be further purified by column chromatography.

Similarly when an appropriate amount of6-amino-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid is substituted for3-[(acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid in the above procedure,6-[[2-[4-(isothioureamethyl)phenyl]acetyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid is obtained.

When in the above described procedure appropriate amounts of thecephalosporin derivative and the isothiourea derivative as the acidchloride hydrochloride listed below in Table XII are substitutedrespectively for3-[(acetyloxy)-methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid and p-isothioureamethylphenylacetic acid the respective products inTable XII are obtained.

                                      TABLE XII                                   __________________________________________________________________________    Cephalosporin Derivative                                                                          Isothiourea Derivative                                                                            Product                               __________________________________________________________________________    3-[(acetyloxy)methyl]-7-amino-8-oxo-                                                              p-isothioureamethyl-2-                                                                      3-[(acetyloxy)methyl]-7-[[3-[4-iso-         5-thia-1-azabicyclo[4.2.0]oct-2-ene-                                                              methylhydrocinnamic                                                                         thioureamethyl)phenyl]-2-methylpro-         2-carboxylic acid propionyloxymethyl                                                              acid          pionyl]amino]-8-oxo-5-thia-1-azabi-         ester                             cyclo[4.2.0]oct-2-ene-2-carboxylic                                            acid propionyloxymethyl ester               3-[(acetyloxy)methyl]-7-amino-8-oxo-                                                              4-(p-n-propylisothio-                                                                       3-[(acetyloxy)methyl]-7-[[4-[4-(n-          5-thia-1-azabicyclo[4.2.0]oct-2-ene-                                                              ureamethylphenyl)butyric                                                                    propylisothioureamethyl)phenyl]butyryl]-                                      4                                           2-carboxylic acid pivalyloxymethyl                                                                acid          amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]-    ester                             oct-2-ene-2-carboxylic acid                                                   pivalyloxy-                                                                   methyl ester                                3-[(acetyloxy)methyl]-7-amino-8-oxo-                                                              p-isothioureamethyl-                                                                        3-[(acetyloxy)methyl]-7-[[2-[4-(p-iso-      5-thia-1-azabicyclo[4.2.0]oct-2-ene-                                                              phenoxyacetic acid                                                                          thioureamethyl)phenoxy]acetyl]amino]-       2-carboxylic acid pivalyloxybenzyl                                                                              8-oxo-5-thia-1-azabicyclo[4.2.0]oct-        ester                             2-ene-2-carboxylic acid pivalyloxy-                                           benzyl ester                                3-[(acetyloxy)methyl]-7-amino-8-oxo-                                                              2-[p-(1,1-diethyl-3-                                                                        3-[(acetyloxy)methyl]-7-[[3-[4-(1,1-        5-thia-1-azabicyclo[4.2.0]oct-2-ene-                                                              methylisothioureamethyl)-                                                                   diethyl-3-methylisothioureamethyl)-         2-carboxylic acid 2-amino-3-methyl-                                                               phenoxy]propionic acid                                                                      phenoxy]propionyl]amino]-8-oxo-5-thia-      butyryloxymethyl ester            1-azabicyclo[4.2.0]oct-2-ene-2-car-                                           boxylic acid 2-amino-3-methylbutyryl-                                         oxymethyl ester                             3-[(acetyloxy)methyl]-7-amino-8-oxo                                                               4-(p-isothioureamethyl-                                                                     3-[(acetyloxy)methyl]-7-[[4-[4-(isothio-    5-thia-1-azabicyclo[4.2.0]oct-2-ene-                                                              phenoxy)butyric acid                                                                        ureamethyl)phenoxy]butyryl]amino]-8-oxo-    carboxylic acid N-ethoxycarbonyl-N-                                                                             5-thia-1-azabicyclo[4.2.0]oct-2-ene-        methylaminomethyl ester           2-carboxylic acid N-ethoxycarbonyl-N-                                         methylaminomethyl ester                     3-(2-methyl-1,3,4-thiadiazol-5-yl-                                                                2-(p-isothioureamethyl)-                                                                    3-(2-methyl-1,3,4-thiadiazol-5-ylthio)-     thio)-7-amino-8-oxo-5-thia-1-azabi-                                                               anilinopropionic acid                                                                       7-[[3-[4-(isothioureamethyl)anilino]-       cyclo[4.2.0]oct-2-ene-2-carboxylic                                                                              propionyl]amino]-8-oxo-5-thia-1-azabi-      acid                              cyclo[4.2.0]oct-2-ene-2-carboxylic                                            acid                                        3-(1-methyltetrazol-5-ylthio)-7-                                                                  4-(p-n-propylisothio-                                                                       3-(1-methyltetrazol-5-ylthio)-7-[[4-[4-     amino-8-oxo-5-thia-1-azabicyclo-                                                                  ureamethylanilino]-                                                                         n-propylisothioureamethyl)anilino]-         [4.2.0]oct-2-ene-2-carboxylic                                                                     butyric acid  butyryl]amino]-8-oxo-5-thia-1-azabicy-      acid                              clo[4.2.0]oct-2-ene-2-carboxylic acid       3-[(acetyloxy)methyl]-7-amino-8-                                                                  p-(1-ethyl-3-methyliso-                                                                     3-[(acetyloxy)methyl]-7-[[2-[4-(1-          oxo-5-thia-1-azabicyclo[4.2.0]-                                                                   thioureamethyl)phenyl-                                                                      ethyl-3-methylisothioureamethyl)phenyl-     oct-2-ene-2-carboxylic acid                                                                       thioacetic acid                                                                             thio]acetyl]amino]-8-oxo-5-thia-1-aza-                                        bicyclo[4.2.0]oct-2-ene-2-carboxylic                                          acid                                        3-(3-methyl-1,3,4-thiadiazol-5-yl-                                                                *2-amino-4-(p-isothio-                                                                      3-(3-methyl-1,3,4-thiadiazol-5-ylthio)-                                       N                                           thio)-7-amino-8-oxo-5-thia-1-aza-                                                                 ureamethylphenyl)buty-                                                                      7-[[4-[4-(isothioureamethyl)phenyl]2-       bicyclo[4.2.0]oct-2-ene-2-carbox-                                                                 ric acid      aminobutyryl]amino]-8-oxo-5-thia-1-         ylic acid pivalyloxymethyl ester  azabicyclo[4.2.0]oct-2-ene-2-carbox-                                          ylic acid pivalyloxymethyl ester            3-[(acetyloxy)methyl]-7-amino-8-                                                                  *2-amino-4-(p-isothio-                                                                      3-[(acetyloxy)methyl]-7-[[4-[4-(iso-        oxo-5-thia-1-azabicyclo[4.2.0]-                                                                   ureamethylphenoxy)-                                                                         thioureamethyl)phenoxy]-2-aminobutyryl]-                                      O                                           oct-2-ene-2-carboxylic acid                                                                       butyric acid  amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]-                                      oct-2-ene-2-carboxylic                      __________________________________________________________________________                                      acid.                                        *The amino group is protected by a suitable blocking group, such as           tert-butoxycarbonyl, prior to coupling and the protecting group is remove     from the reaction product by procedures known in the art.                

EXAMPLE 353-(2-Methyl-1,3,4-thiadiazol-5-ylthio)-7-[[2-[4-(isothioureamethyl)phenyl]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

A solution of 3 mM of3-[(acetyloxy)-methyl]-7-[[2-[4-(isothioureamethyl)phenyl]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid in 100 ml of water is treated with 3 mM of sodium bicarbonate and 6mM of 2-methyl-1,3,4-thiadiazol-5-ylthio at 70° C under nitrogen for31/2 hours. The water is removed in vacuo and the residue is taken up inmethanol. A large excess of acetonitrile is added to precipitate theproduct which is isolated by filtration and dried in a vacuum desiccatorto give3-(2-methyl-1,3,4-thiadiazol-5-ylthio)-7-[[2-[4-(isothioureamethyl)phenyl]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid.

When appropriate amounts of the cephalosporin derivatives and the thiolderivatives listed below in Table XIII are substituted for thecephalosporin derivative and thiol derivative in the above procedure therespective products listed in Table XIII are obtained:

                                      TABLE XIII                                  __________________________________________________________________________    Cephalosporin Derivative                                                                              Thiol Derivative  Product                             __________________________________________________________________________    3-[(acetyloxy)methyl]-7-[[3-[4-(iso-                                                                1-methyltetrazol-5-ylthiol                                                                   3-(1-methyltetrazol-5-ylthio)-7-         thioureamethyl)phenylthio]-2-amino-  [[3-[4-(isothioureamethyl)phenyl-        propionyl]amino]-8-oxo-5-thia-1-aza- thio]-2-aminopropionyl]amino]-8-         bicyclo[4.2.0]oct-2-ene-2-carboxylic oxo-5-thia-1-azabicyclo[4.2.0]oct-       acid                                 2-ene-2-carboxylic acid                  3-[(acetyloxy)methyl]-7-[[3-[4-(1,3-                                                                2-methyl-1,3,4-thiadiazol-                                                                   3-(2-methyl-1,3,4-thiadiazol-5-yl-       di-n-propylisothioureamethyl)anilino]-                                                              5-ylthiol      thio)-7-[[3-[4-(1,3-di-n-propyliso-      2-carboxypropionyl]amino]-8-oxo-5-thia-                                                                            thioureamethyl)anilino]-2-carboxy-       1-azabicyclo[4.2.0]oct-2-ene-2-carbox-                                                                             propionyl]amino]-8-oxo-5-thia-1-         ylic acid                            azabicyclo[4.2.0]oct-2-ene-2-car-                                             boxylic acid                             3-[(acetyloxy)methyl]-7-[[2-[4-(1-                                                                  3-methyl-1,2,4-thiadiazol-                                                                   3-(3-methyl-1,2,4-thiadiazol-5-yl-       methyl-3-ethylisothioureamethyl)-                                                                   5-ylthio       thio)-7-[[2-[4-(1-methyl-3-ethyl-        phenyl]-2-sulfoacetyl]amino]-8-oxo-  isothioureamethyl)phenyl]-2-sulfo-       5-thia-1-azabicyclo[4.2.0]oct-2-     acetyl]amino]-8-oxo-5-thia-1-aza-        ene-2-carboxylic acid                bicyclo[4.2.0]oct-2-ene-2-carbox-                                             ylic acid                                3-[(acetyloxy)methyl]-7-[[3-[4-(1,3-                                                                tetrazol-5-ylthiol                                                                           3-(tetrazol-5-ylthio)-7-[[3-[4-(1,3-                                          N                                        diethylisothioureamethyl)phenyl]-2-  diethylisothioureamethyl)phenyl]-2-      hydroxypropionyl]amino]-8-oxo-5-thia-                                                                              hydroxypropionyl]amino]-8-oxo-5-thia-                                         O                                        1-azabicyclo[4.2.0]oct-2-ene-2-car-  1-azabicyclo[4.2.0]oct-2-ene-2-car-      boxylic acid                         boxylic acid                             3-[(acetyloxy)methyl]-7-[[3-[4-(iso-                                                                2-methyl-1,3,4-oxa-                                                                          3-(2-methyl-1,3,4-oxadiazol-5-yl-        thioureamethyl)anilino]-2-methyl-                                                                   diazol-5-ylthiol                                                                             thio)-7-[[3-[ 4-(isothioureamethyl)-     propionyl]amino]-8-oxo-5-thia-1-     anilino]-2-methylpropionyl]amino]-       azabicyclo[4.2.0]oct-2-ene-2-car-    8-oxo-5-thia-1-azabicyclo[4.2.0]-        boxylic acid                         oct-2-ene-2-carboxylic acid              3-[(acetyloxy)methyl]-7-[[2-[4-(iso-                                                                2-methyl-1,3,4-thiadiazol                                                                    3-(2-methyl-1,3,4-thiadiazol-5-yl-       thioureamethyl)phenoxy]acetyl]amino]-                                                               5-ylthiol      thio)-7-[[2-[4-(isothioureamethyl)-      8-oxo-5-thia-1-azabicyclo[4.2.0]-    phenoxy]acetyl]amino]-8-oxo-5-thia-      oct-2-ene-2-carboxylic acid          1-azabicyclo[4.2.0]oct-2-ene-2-                                               carboxylic acid                          3-[(acetyloxy)methyl]-7-[[2-[4-(1,1-                                                                1-methyltetrazol-5-ylthiol                                                                   3-(1-methyltetrazol-5-ylthio)-7-         diethyl-3-methylisothioureamethyl)-  [[2-[4-(1,1-diethyl-3-methyliso-         phenyl]-2-methylacetyl]amino]-8-oxo- thioureamethyl)phenyl]-2-methyl-         5-thia-1-azabicyclo[4.2.0]oct-2-ene- acetyl]amino]-8-oxo-5-thia-1-aza-        2-carboxylic acid                    bicyclo[4.2.0]oct-2-ene-2-carbox-                                             ylic acid                                3-[(acetyloxy)methyl]-7-[[2-[4-(iso-                                                                2-methyl-1,3,4-thiadiazol-                                                                   3-(2-methyl-1,3,4-thiadiazol-5-yl-       thioureamethyl)phenyl]-2-carboxy-                                                                   5-ylthiol      thio)-7-[[2-[4-(isothioureamethyl)-      acetyl]amino]-8-oxo-5-thia-1-azabi-  phenyl]-2-carboxyacetyl]amino]-8-        cyclo[4.2.0]oct-2-ene-2-carboxylic   oxo-5-thia-1-azabicyclo[4.2.0]oct-       acid                                 2-ene-2-carboxylic                       __________________________________________________________________________                                         acid                                 

EXAMPLE 36

When in the procedure of Example 14 appropriate amounts of3-(2-methyl-1,3,4-thiadiazol-5-ylthio)-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid or3-(1-methyltetrazol-5-ylthio)-7-amino-8-oxo5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid are substituted for3-acetyloxymethyl-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid and 2-sulfo-p-chloromethylphenylacetyl chloride prepared from thecorresponding acid is substituted for p-chloromethylphenylacetylchloride the following respective products are obtained.3-(2-methyl-1,3,4-thiadiazol-5-ylthio)-7-[[2-[4-(chloromethyl)phenyl]-2-sulfoacetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid and3-(1-methyltetrazol-5-ylthio)-7-[[2-[4-(chloromethyl)phenyl]-2-sulfoacetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid.

When in the procedure of Example 27 an appropriate amount of each of theabove obtained chloromethyl substituted cephalosporin derivatives issubstituted for3-[(acetyloxy)methyl]-7-[[2-[4-(chloromethyl)phenyl]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid the following respective products are obtained:

3-(2-methyl-1,3,4-thiadiazol-5-ylthio)-7-[[2-[4-isothioureamethyl)phenyl]-2-sulfoacetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid and3-(1-methyltetrazol-5-ylthio)-7-[[2-[4-(isothioureamethyl)-phenyl]-2-sulfoacetyl]amino]-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylicacid.

We claim:
 1. A compound selected from a base of the formula##SPC14##wherein Aryl is selected from phenyl or 2-thienyl; Y isselected from hydrogen, chlorine, bromine, a straight or branched loweralkyl group of from 1 to 4 carbon atoms, or an alkoxy group of from 1 to4 carbon atoms with the proviso that when Aryl is 2-thienyl, Y ishydrogen; each of R¹, R² and R³ is selected from hydrogen or a straightor branched lower alkyl group of from 1 to 4 carbon atoms; Z is selectedfrom a bond, oxygen, sulfur or imino with the proviso that when Aryl is2-thienyl, Z is a bond; W is selected from hydrogen, methyl, anino,hydroxy, SO₃ H, or COOR⁴ wherein R⁴ is selected from hydrogen or5-indanyl; n is zero, 1 or 2 with the proviso that when W is other thanhydrogen or methyl and Z is other than a bond, n is not zero; R⁵ isselected from hydrogen or methoxy; M is selected from hydrogen, apharmaceutically acceptable non-toxic cation charge, analkanoyloxymethyl group wherein the alkanoyl moiety has from 1 to 5carbon atoms and may be straight or branched, an alkanoylaminomethylgroup wherein the alkanoyl moiety has from 1 to 5 carbon atoms and maybe straight or branched and wherein the amino nitrogen may besubstituted with an alkyl group of from 1 to 4 carbon atoms, analkoxycarbonylaminomethyl group wherein the alkoxy moiety has from 1 to4 carbon atoms and may be straight or branched and wherein the aminonitrogen may be substituted with an alkyl group of from 1 to 4 carbonatoms, p-(alkanoyloxy)benzyl wherein the alkanoyl moiety contains from 1to 5 carbon atoms and may be straight or branched oraminoalkanoyloxymethyl as represented by the group ##EQU1## wherein n'is 0 to 5, each of R¹¹ and R¹² is selected from hydrogen or lower alkylof from 1 to 4 carbon atoms, and each of R¹³ and R¹⁴ is selected fromhydrogen or a straight or branched lower alkyl group of from 1 to 4carbon atoms; and pharmaceutically acceptable salts thereof.
 2. Acompound of claim 1 wherein W is hydrogen.
 3. A compound of claim 2wherein Z is a bond.
 4. A compound of claim 2 wherein Z is oxygen orsulfur.
 5. A compound of claim 2 wherein Z is imino.
 6. A compound ofclaim 1 wherein W is methyl.
 7. A compound of claim 6 wherein Z is abond.
 8. A compound of claim 6 wherein Z is oxygen or sulfur.
 9. Acompound of claim 6 wherein Z is imino.
 10. A compound of claim 1wherein W is hydroxy.
 11. A compound of claim 10 wherein Z is a bond.12. A compound of claim 10 wherein Z is oxygen or sulfur.
 13. A compoundof claim 10 wherein Z is imino.
 14. A compound of claim 1 wherein W isamino.
 15. A compound of claim 14 wherein Z is a bond.
 16. A compound ofclaim 14 wherein Z is oxygen or sulfur.
 17. A compound of claim 14wherein Z is imino.
 18. A compound of claim 1 wherein W is COOR⁴ or SO₃H.
 19. A compound of claim 18 wherein Z is a bond.
 20. A compound ofclaim 18 wherein Z is oxygen or sulfur.
 21. A compound of claim 18wherein Z is imino.